WO2022059778A1 - Cyclic urea derivative - Google Patents

Cyclic urea derivative Download PDF

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Publication number
WO2022059778A1
WO2022059778A1 PCT/JP2021/034326 JP2021034326W WO2022059778A1 WO 2022059778 A1 WO2022059778 A1 WO 2022059778A1 JP 2021034326 W JP2021034326 W JP 2021034326W WO 2022059778 A1 WO2022059778 A1 WO 2022059778A1
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WIPO (PCT)
Prior art keywords
group
substituent
pharmaceutically acceptable
acceptable salt
urea derivative
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PCT/JP2021/034326
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French (fr)
Japanese (ja)
Inventor
綾子 澤
里奈 長尾
亘 川畑
匡明 澤
康弘 岩田
春菜 永尾
啓江 中山
優子 朝光
英樹 森山
Original Assignee
カルナバイオサイエンス株式会社
大日本住友製薬株式会社
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Application filed by カルナバイオサイエンス株式会社, 大日本住友製薬株式会社 filed Critical カルナバイオサイエンス株式会社
Publication of WO2022059778A1 publication Critical patent/WO2022059778A1/en

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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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Definitions

  • the present invention relates to pharmaceuticals, in particular novel cyclic urea derivatives having DYRK inhibitory activity or pharmaceutically acceptable salts thereof.
  • DYRK Dual-specificity tYrosine-phosphorylation regulated protein kinase
  • DYRK functions as a tyrosine kinase only in the case of autophosphorylation and catalyzes the phosphorylation of serine or threonine residues to exogenous substrates.
  • Five known members of the DYRK family, DYRK1A, DYRK1B, DYRK2, DYRK3 and DYRK4 are known in humans (Non-Patent Document 1).
  • DYRK1A has been widely reported to be associated with neuropsychiatric disorders. For example, in patients with Alzheimer's disease, ⁇ -amyloid expression and DYRK1A expression are significantly consistent (Non-Patent Document 2), and abnormal phosphorylation of tau protein (Tau), which is considered to contribute to the onset of Alzheimer's disease. It is presumed that DYRK1A is involved in this (Non-Patent Document 3).
  • Parkinson's disease is a neurodegenerative disease caused by degeneration of dopaminergic nerves, which are important for motor function, and one of the causes is considered to be mitochondrial dysfunction (Non-Patent Document 4).
  • An enzyme involved in proteolysis called parkin is known to have a function of metabolizing abnormal mitochondria and suppressing abnormal accumulation, and DYRK1A has been reported to suppress the activity of this parkin protein (non-patent document). 5).
  • Non-Patent Document 6 The gene for DYRK1A is located in the critical region of Down's syndrome, and it has been reported that mice overexpressing DYRK1A cause abnormalities in neuropsychiatric function and exhibit Down's syndrome. In addition, it has been reported that DYRK1A expression is increased in the brains of Down's syndrome patients and Down's syndrome-like model mice (Non-Patent Document 7). These facts suggest that DYRK1A is involved in the onset of neurological symptoms in Down's syndrome patients (Non-Patent Document 8).
  • Non-Patent Document 8 since it has been reported that juvenile Alzheimer's disease frequently occurs in Down's syndrome patients, it can be seen that DYRK1A is closely related to Alzheimer's disease (Non-Patent Document 8). Therefore, compounds that inhibit DYRK1A are considered to be useful in the treatment of neuropsychiatric disorders such as Alzheimer's disease, Down's disease, mental retardation, memory impairment, memory loss and Parkinson's disease. Recently, it has been reported that DYRK1A is highly expressed in brain tumors such as glioblastoma, and that DYRK1A regulates the expression of EGFR (Non-Patent Document 9). Therefore, the compound that inhibits DYRK1A is considered to be useful for the treatment of EGFR-dependent cancer by suppressing the growth of cancer cells in epidermal growth factor receptor (EGFR) -dependent brain tumors and tumors.
  • EGFR epidermal growth factor receptor
  • Non-Patent Document 10 telogen (G0 phase) cancer cells and contributes to resistance to various chemotherapeutic agents. It has also been reported that inhibition of DYRK1B promotes withdrawal from the G0 phase and improves sensitivity to chemotherapeutic agents. Therefore, the compound that inhibits DYRK1B is considered to be useful for the treatment of pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer and lung cancer (Non-Patent Documents 11, 12, 13, 14, 15).
  • Non-Patent Document 16 It has been suggested that DYRK2 regulates p53 in response to DNA damage and induces apoptosis. Furthermore, compounds that inhibit DYRK3 have been reported to be useful in the treatment of sickle cell anemia and chronic kidney disease (Non-Patent Document 17). In addition to Patent Document 1 as a compound that inhibits DYRK, Patent Document 2 is reported as an inhibitor of DYRK1A and DYRK1B. However, the cyclic urea derivative of the present invention is not described.
  • An object of the present invention is to provide a pharmaceutical product, particularly a novel compound having a DYRK inhibitory effect.
  • the object of the present invention is achieved by the following (1) to (23).
  • RA , RB, RC and RD each independently represent a hydrogen atom or a C 1-6 alkyl group.
  • a 1 and A 2 together with the bonded aromatic ring and linker L form a saturated or unsaturated tricyclic condensed ring, respectively.
  • R 1 is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, and an aryl which may have a substituent. Represents a group, a heteroaryl group which may have a substituent, and a saturated heterocyclic group which may have a substituent.
  • R 2 represents a hydrogen atom or a methyl group.
  • R 1 has a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, and a phenyl group which may have a substituent.
  • R 1 is represented by -CH 2 NR 3 R 4 or -CH 2 OR 5 .
  • R 3 and R 4 are independently hydrogen atom, C 1-6 alkyl group (may be further substituted with hydroxy group), C 2-6 alkynyl group, C 2-6 alkenyl group, C 3 Represents a -6 cycloalkyl group, a C 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 together with the nitrogen atom to which they are attached. May contain 1 to 2 oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms, and may have substituents, 4 to 10 member monocyclic or two.
  • a cyclic saturated cyclic amino group may be formed, R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
  • R 1 is a phenyl group which may have a substituent or a pyridyl group which may have a substituent, and the substituents are a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and the like. 1 to 3 substituents selected from the group consisting of hydroxymethyl groups, The cyclic urea derivative according to (4) above or a pharmaceutically acceptable salt thereof;
  • R 1 is represented by -CH 2 NR 3 R 4 or -CH 2 OR 5 .
  • R 3 and R 4 are independently hydrogen atom, C 1-6 alkyl group (may be further substituted with hydroxy group), C 2-6 alkynyl group, C 2-6 alkenyl group, C 3 Represents a -6 cycloalkyl group, a C 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 together with the nitrogen atom to which they are attached. May contain 1 to 2 oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms, and may have substituents, 4 to 10 member monocyclic or two.
  • a cyclic saturated cyclic amino group may be formed, R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
  • R 1 is a phenyl group which may have a substituent or a pyridyl group which may have a substituent, and the substituents are a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and the like.
  • R 1 is 1) hydrogen. atom, 2) C 1-6 alkyl group, which may be substituted with a cyano group, 3) Represented by -CH 2 NR 3 R 4 or -CH 2 OR 5
  • R 3 and R 4 are a hydrogen atom, a C 1-6 alkyl group (which may be further substituted with a hydroxy group), a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, and a C.
  • a 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 are combined with the nitrogen atom to which they are attached, 1-2.
  • 5- to 10-membered monocyclic or bicyclic saturated cyclic amino groups which may contain substituents, may contain oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms.
  • the saturated cyclic amino group may be composed of a halogen atom, an oxo group, a methoxy group, a hydroxy group, a hydroxymethyl group, a carboxy group, a methoxycarbonyl group, a dimethylcarbamoyl group, a methylcarbamoyl group, and a difluoromethyl group. May be substituted with one or two substituents selected from the group of R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
  • DYRK Diseases associated with DYRK are frontotemporal dementia, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, Levy body dementia, vascular dementia, traumatic brain injury, chronic traumatic Encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down's disease, depression and associated mental retardation, memory impairment, memory loss, learning impairment, intellectual disability, cognitive dysfunction, mild cognitive impairment, dementia symptoms or brain tumor, pancreatic cancer , Ovarian cancer, osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis sickle red erythrocyte anemia, chronic renal disease or bone resorption disease, the therapeutic agent and / or the prophylactic agent according to (17) above.
  • the present invention comprises administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of (1) to (14) above, or a pharmaceutically acceptable salt thereof.
  • a method for treating and / or preventing a disease involving DYRK. (20) The cyclic urea derivative according to any one of (1) to (14) above, or pharmaceutically acceptable thereof, for producing a therapeutic agent and / or a preventive agent for a disease involving DYRK. Use of salt.
  • (21) The cyclic urea derivative according to any one of (1) to (14) above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of diseases associated with DYRK. ..
  • the compounds provided by the present invention include diseases known to be associated with DYRK1A-mediated aberrant cellular responses, such as mental and neurological disorders such as Alzheimer's disease, Parkinson's disease, Down's disease, depression, as well.
  • diseases known to be associated with DYRK1A-mediated aberrant cellular responses such as mental and neurological disorders such as Alzheimer's disease, Parkinson's disease, Down's disease, depression, as well.
  • the compound provided by the present invention is useful as an inhibitor of DYRK1B as a prophylactic or therapeutic drug (pharmaceutical composition) for tumors such as pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, and lung cancer. Furthermore, the compound provided by the present invention is useful as a prophylactic or therapeutic drug (pharmaceutical composition) for bone resorption disease and osteoporosis because it controls p53 in response to DNA damage and induces apoptosis of DYRK2. be. Further, the compound provided by the present invention is useful as an inhibitor of DYRK3 as a prophylactic or therapeutic drug (pharmaceutical composition) for sickle cell anemia, chronic kidney disease, bone resorption disease and osteoporosis. Further, as a compound that inhibits DYRK, it is useful as a reagent for pathological imagery related to the above-mentioned diseases and a reagent for basic experiments and research.
  • the novel cyclic urea derivative of the present invention has the following formula (I):
  • RA , RB, RC and RD each independently represent a hydrogen atom or a C 1-6 alkyl group.
  • R 1 is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, and an aryl which may have a substituent.
  • R 2 represents a hydrogen atom or a methyl group. ) It is a compound indicated by.
  • the ring portion composed of A 1 , A 2 and the linker L contains at least one hetero atom selected from a nitrogen atom and an oxygen atom, and has a substituent.
  • a good saturated or unsaturated hetero 5-membered or hetero 6-membered ring is exemplified.
  • RA a hydrogen atom or a methyl group is exemplified.
  • the ring portion composed of A 1 and A 2 and the linker L is condensed with a benzothiazole ring and, for example, dihydrobenzoflotiazole, dioxolobenzothiazole, quinolinothiazole, quinoxalinothiazole.
  • Imidazobenzothiazole, thiazoloinazole, thiazolobenzoxazole, thiazolobenzoxazine, thiazolobenzoxazineone, and the like are exemplified.
  • the linker L is preferably methylene, A 2 is preferably an oxygen atom or CR CRD , and RC and R D are particularly preferably hydrogen atoms.
  • the linker L is preferably ethylene and A 2 is preferably NR A , and RA is particularly preferably C 1-6 alkyl, particularly methyl.
  • the linker L is a nitrogen atom or methine, and A 2 is preferably NR A , in which case RA is preferably methyl.
  • linker L is preferably ethandylidene and A 2 is preferably NRA or CR B.
  • RA is preferably a hydrogen atom and RB is preferably methyl.
  • DYRK represents Dual-specificity tYrosine-phosphorylated protein kinase, and means one of the DYRK family (DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4 or more).
  • alkyl group which may have a substituent examples include a linear or branched alkyl group having 1 to 6 carbon atoms (C 1-6 alkyl group), and specifically, a methyl group. , Ethyl group, n-propyl group, isopropyl group, tert-butyl group and the like.
  • the C 1-4 alkyl group represents a linear or branched alkyl group having 1 to 4 carbon atoms.
  • alkenyl group which may have a substituent examples include a linear or branched alkenyl group having 2 to 6 carbon atoms (C 2-6 alkenyl group), and specifically, a vinyl group.
  • alkynyl group which may have a substituent include a linear or branched alkynyl group having 2 to 6 carbon atoms (C 2-6 alkynyl group), and specifically, an ethynyl group. , 2-Propinyl group, 2-Butynyl group and the like.
  • Examples of the cycloalkyl group which may have a substituent include a cycloalkyl group having 3 to 6 carbon atoms (C 3-6 cycloalkyl group), for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. And so on.
  • Examples of the aryl group which may have a substituent include an aryl group having 6 to 14 carbon atoms, and specific examples thereof include a phenyl group.
  • Specific examples of the heteroaryl group which may have a substituent include a 5- or 6-membered heteroaryl group containing at least one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • Examples thereof include a thienyl group, a frill group, a pyrrol group, a pyridyl group and the like, and the pyridyl group is most preferable.
  • Examples of the saturated heterocyclic group which may have a substituent include a 4- to 6-membered monocyclic saturated heterocyclic group containing at least one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom. Specific examples thereof include an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group and the like.
  • the "substituent" of the alkyl group which may have a substituent, the alkenyl group which may have a substituent and the cycloalkyl group which may have a substituent may be 1 or 2. Any kind of substituents of any kind may be present at any position chemically possible, and when there are two or more substituents, the substituents may be the same or different. .. Specific examples of the substituent are represented by C 3-6 cycloalkyl group, halogen atom, C 1-4 alkoxy group, cyano group, benzyloxy group, phenyl group, hydroxy group, methanesulfonyl group and -NR 3 R 4 .
  • the substituted or unsubstituted amino group to be substituted is exemplified.
  • R 1 the alkyl group which may have a substituent can also be represented by -CH 2 NR 3 R 4 or -CH 2 OR 5 .
  • R 3 and R 4 are independently hydrogen atom, C 1-6 alkyl group (for example, methyl group), C 2-6 alkenyl group (for example, vinyl group, allyl group), C 2-6 alkynyl.
  • C 1-6 alkyl group may be further substituted with a hydroxy group, a phenyl group, a cyano group, a halophenyl group or the like. Further, the C 1-6 acyl group may be substituted with a hydroxy group.
  • R 3 and R 4 combine with the nitrogen atom to which they bind and may contain one or two oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms, substituents. It constitutes a 4- to 10-membered monocyclic or bicyclic saturated cyclic amino group that may have.
  • Specific examples of the saturated cyclic amino group include monocyclic cyclic amino groups such as azetinidyl group, pyrrolidinyl group, piperazinyl group, homopiperidinyl group, morpholinyl group, 1,4-oxazepanyl group and thiomorpholinyl group; (tetrahydro-1H-flow).
  • Bicyclic amino groups include halogen atoms, methyl groups, oxo groups, methoxy groups, hydroxy groups, hydroxymethyl groups, hydroxyisopropyl groups, carboxy groups, methoxycarbonyl groups and dimethylcarbamoyl groups.
  • Methylcarbamoyl group and difluoromethyl group may be substituted with 1 to 3 substituents selected from the group.
  • R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
  • the "substituted group" of the aryl group which may have a substituent, the heteroaryl group which may have a substituent, and the saturated heterocyclic group which may have a substituent is 1
  • two or more of any kind of substituents may be present at any chemically possible position, and when there are two or more substituents, the respective substituents may be the same but different. May be good.
  • Specific examples of the substituent include a halogen atom, a vinyl group, a methyl group, a methoxy group, a cyano group, a hydroxy group, a hydroxymethyl group and the like.
  • the substituent R 1 is 1) Hydrogen atom, 2) C 1-6 alkyl group, which may be substituted with a cyano group, 3) Represented by -CH 2 NR 3 R 4 or -CH 2 OR 5
  • R 3 and R 4 are a hydrogen atom, a C 1-6 alkyl group (which may be further substituted with a hydroxy group), a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, and a C.
  • a 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 are combined with the nitrogen atom to which they are attached, 1-2.
  • 5- to 10-membered monocyclic or bicyclic saturated cyclic amino groups which may contain substituents, may contain oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms.
  • the saturated cyclic amino group may be composed of a halogen atom, an oxo group, a methoxy group, a hydroxy group, a hydroxymethyl group, a carboxy group, a methoxycarbonyl group, a dimethylcarbamoyl group, a methylcarbamoyl group, and a difluoromethyl group. May be substituted with one or two substituents selected from the group of R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
  • the cyclic urea derivative (I) or a pharmaceutically acceptable salt thereof is preferred.
  • the pharmaceutically acceptable salts of the compound (I) of the present invention include inorganic acid salts with hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid and the like, fumaric acid, maleic acid, methanesulfonic acid and p-toluenesulfonic acid. And the like, organic acid salts and the like can be mentioned.
  • ammonium salts and the like are also included in the present invention.
  • the compound (I) of the present invention may have an isomer, for example, depending on the type of substituent. In the present specification, only one form of these isomers may be described as a chemical structure, but in the present invention, all isomers (geometric isomers, steric isomers, remutable isomers) that may occur structurally are described.
  • the compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced, for example, by the following method.
  • a method usually used in synthetic organic chemistry for example, a functional group. Protection, deprotection [T. W. Greene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, lnc. , 1999] and the like, it can be easily manufactured.
  • the order of reaction steps such as introduction of substituents can be changed as needed.
  • the compound (I) of the present invention deprotects the compound (II) and then reacts with a condensing agent such as 1,1'-carbonyldiimidazole (CDI) or dicarbonate (N-succinimidyl) (DSC) in a solvent.
  • a condensing agent such as 1,1'-carbonyldiimidazole (CDI) or dicarbonate (N-succinimidyl) (DSC) in a solvent.
  • CDI 1,1'-carbonyldiimidazole
  • DSC dicarbonate
  • the solvent may be any solvent as long as it is inert to the reaction, and is not particularly limited, but for example, THF, preferably DMF, can be used.
  • the reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several hours, but is preferably synthesized by reacting in DMF at room temperature for 30 minutes.
  • the compound (II) used as a raw material of Scheme 1 can be produced, for example, by the method shown in Scheme 2.
  • a 1 , A 2 , L, R 1 and R 2 have the same meaning as described in (I) above, and PG represents a protecting group.
  • Compound (II) is also produced, for example, by reacting thiourea (V) obtained by reacting isothiocyanate (III) with amine (IV) in a solvent with a bromine or a brominated reagent to form a thiazole ring.
  • isothiocyanate (III) is mixed with 1 to 1.5 molar equivalent amine (IV) with respect to isothiocyanate (III) in a solvent such as ethanol in the presence or absence of a base such as sodium ethoxide.
  • Thiourea (V) is obtained by reacting.
  • the reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several days, but is preferably synthesized by reacting at room temperature for one day.
  • Compound (II) can be obtained by reacting with a brominated reagent such as 0.9 to 1 molar equivalent of benzyltrimethylammonium tribromid.
  • the reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several days, but is preferably synthesized by reacting at room temperature for one day.
  • the isothiocyanate (III) and amine (IV) used as raw materials for Scheme 2 can be obtained as commercial products, or can be produced by a known method or a method usually used in synthetic organic chemistry.
  • Compound (II) is prepared by forming a thiazole ring by Ullman-type condensation in a solvent of thiourea (VII) obtained by reacting, for example, isothiocyanate (VI) with amine (IV), and then deprotecting the compound (II).
  • a solvent of thiourea VII
  • a base such as sodium ethoxide.
  • the reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several days, but is preferably synthesized by reacting at room temperature for one day.
  • the isothiocyanate (VI) used as a raw material of Scheme 3 can be obtained as a commercial product, or can be produced by a known method or a method usually used in synthetic organic chemistry.
  • the compound (II) used as a raw material of Scheme 1 can also be produced, for example, by the method shown in Scheme 4.
  • Compound (II) can be produced, for example, by reacting compound (VIII) with an amine (IV) in a solvent such as THF, acetonitrile or DMA or in the absence of a solvent.
  • a solvent such as THF, acetonitrile or DMA or in the absence of a solvent.
  • it can be produced by reacting compound (VIII) with 3-10 molar equivalents of amine (IV).
  • the reaction can be carried out in the range of room temperature to 150 ° C. for several minutes to several days, but the compound (II) can be synthesized by reacting at 120 ° C. for one day.
  • the stereoisomer (II') of the compound (II) is synthesized by using the stereoisomer (IV') of the amine, and the scheme 1
  • the desired product can be obtained by carrying out the reaction according to the above.
  • a 1 , A 2 , L, R 1 , and R 2 have the same meaning as described in (I) above, and PG represents a protecting group.
  • compound (VIII) used as a raw material of Scheme 4 can be produced, for example, by the method shown in Scheme 5.
  • a 1 , A 2 and L are synonymous with the description in (I) above, R represents an alkyl group, and R-X represents an alkyl halide.
  • compound (X) can be produced by reacting compound (IX) with carbon dioxide in a solvent in the presence of a strong base.
  • a strong base for example, it can be obtained by blowing carbon dioxide gas into a solvent such as THF and in the presence of a strong base such as LDA.
  • the reaction can be carried out in the range of ⁇ 80 ° C. to ⁇ 70 ° C.
  • the compound (IX) used as a raw material can be obtained as a commercial product, or can be produced by a known method or a method usually used in synthetic organic chemistry.
  • the carboxyl group of compound (X) can be converted to isocyanate by Curtius rearrangement, and then treated with acid to produce compound (XI).
  • the isocyanate obtained by the Curtius rearrangement can be reacted with tert-butyl alcohol or benzyl alcohol to obtain an amine compound protected by a Boc group or a Z group, which are usually used in synthetic organic chemistry.
  • Compound (XI) can also be produced by deprotection by the method.
  • compound (X) for example, by heating compound (X) with 1.1 to 1.3 molar equivalents of diphenylphosphoryl azide and 8 to 10 molar equivalents of tert-butyl alcohol in a solvent such as dioxane in the presence of a base such as TEA.
  • a compound (XI) in which the amino group is Boc-protected can be obtained.
  • the reaction can be carried out in the range of 100 ° C. to the reflux temperature for 3 hours to 1 day, but can be synthesized by reacting in dioxane at 100 ° C. for 4 hours.
  • compound (XII) can be produced by heating compound (XI) with potassium ethylxanthogenate in a solvent.
  • compound (XII) can be obtained by subjecting compound (XI) to a heat reaction with 2.5 to 3 molar equivalents of potassium ethylxanthogenate in a solvent such as DMF.
  • the reaction can be carried out in the range of 90 ° C. to the reflux temperature for several minutes to several days, but is preferably synthesized by reacting at 120 ° C. for 2 days.
  • the compound (XIII) can be produced by reacting the compound (XII) with an alkyl halide in a solvent in the presence of a base.
  • compound (XIII) is obtained by reacting compound (XII) with an alkyl halide such as ethyl iodide in an amount of 3 to 4 molar equivalents in the presence of a base such as potassium carbonate in a solvent such as DMF. Can be done.
  • the reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several days, but is preferably synthesized by reacting at room temperature for 2 hours.
  • compound (VIII) can be obtained by oxidizing compound (XIII) in a solvent.
  • the solvent may be any one as long as it is inert to the reaction, and is not particularly limited, and for example, acetic acid, water or DCM can be used.
  • the oxidizing agent used in this reaction should be a peroxide such as meta-chloroperbenzoic acid (m-CPBA) or hydrogen peroxide, or an oxidizing agent used in ordinary organic synthesis such as KMnO 4 (potassium permanganate).
  • m-CPBA meta-chloroperbenzoic acid
  • KMnO 4 potassium permanganate
  • 0.8 to 2.5 mol equivalents of m-CPBA or 2 to 2.5 mol equivalents of KMnO 4 can be used with respect to compound (XIII).
  • the reaction can be carried out in the range of 0 ° C. to room temperature for 30 minutes to 2 days, but is preferably synthesized by reacting for 30 minutes under room temperature conditions.
  • the compound (IX) used as a raw material for Scheme 5 can be obtained as a commercial product, or can be produced by a known method or a method usually used in synthetic organic chemistry.
  • the compound (I-1) in which R 1 represents ⁇ CH 2 NR 3 R 4 can be produced, for example, by Scheme 6.
  • a 1 , A 2 , L, R 3 and R 4 have the same meaning as described in (I) above, and X represents a leaving group such as a halogen atom or a substituted sulfonyl group.
  • the compound (I-1) of the present invention causes a nucleophilic substitution reaction of compound (XIV) with an excess amount of 1 to 20 molar equivalents of amine (XV) in a solvent such as THF, acetonitrile or DMA or without a solvent. This makes it possible to obtain compound (I-1).
  • the reaction can be carried out in the range of room temperature to reflux temperature for several hours to several days, but is preferably synthesized by reacting in THF, acetonitrile or a mixed solvent thereof at reflux temperature for 1 day.
  • the amine (XV) used as a raw material for Scheme 6 can be obtained as a commercial product, or can be produced by a known method or a method usually used in synthetic organic chemistry.
  • the above-mentioned compounds (1) to (14) are 5-membered rings or 6-membered compounds in the formulas (I) and (I') together with the aromatic ring and the linker L to which A 1 and A 2 are bonded. Although it is a compound that forms a ring, it can be produced by any of the above-mentioned production methods.
  • Formulations for oral administration include solid preparations such as tablets, granules, powders and capsules, and liquid preparations such as syrup. These formulations can be prepared by conventional methods. Solids can be prepared by using conventional pharmaceutical carriers such as lactose, starch such as cornstarch, crystalline cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, calcium carboxymethyl cellulose, talc, magnesium stearate and the like. can. Capsules can be prepared by encapsulating the granules or powders thus prepared. The syrup is prepared by dissolving or suspending the compound represented by the formulas (I) and (I') of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxymethyl cellulose and the like. Can be prepared.
  • Formulations for parenteral administration include injections such as infusions.
  • Injectable formulations can also be prepared by conventional methods, with isotonic agents (eg, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose), stabilizers (eg, sodium sulfite, etc.). It can be appropriately incorporated into preservatives (eg, benzyl alcohol, methyl p-oxybenzoate).
  • isotonic agents eg, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose
  • stabilizers eg, sodium sulfite, etc.
  • preservatives eg, benzyl alcohol, methyl p-oxybenzoate.
  • the doses of the compounds represented by the formulas (I) and (I') of the present invention or pharmaceutically acceptable salts thereof include the type, severity, age, sex, body weight, dosage form, etc. of the disease. Usually in the range of 1 mg to 1,000 mg per day in adults, which may be administered in one, two or three divided doses by oral or parenteral route. Can be done.
  • the compounds represented by the formulas (I) and the formula (I') of the present invention or pharmaceutically acceptable salts thereof can be used as DYRK inhibitors as reagents for pathological imagery related to the above-mentioned diseases, for basic experiments, and for research. Can be used as a reagent for.
  • the reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure and then dried.
  • a 4M hydrogen chloride-ethyl acetate solution (10 mL, 40 mmol) was added to the ethyl acetate solution (6.0 mL) of this intermediate by ice-cooling, and the mixture was stirred at room temperature for 16 hours.
  • a 2M aqueous sodium hydroxide solution was added to the reaction solution for neutralization, and the mixture was extracted with ethyl acetate.
  • Potassium xanthate (1.2 g, 7.3 mmol) was added to a DMF solution (15 mL) of 3-amino-4-bromo-1,2-methylenedioxybenzene (0.79 g, 3.1 mmol) at room temperature. The mixture was stirred at 120 ° C. for 5 days. Potassium carbonate (2.2 g, mmol) and ethyl iodide (0.76 mL, 9.4 mmol) were added to this reaction solution by ice-cooling, and the mixture was stirred at room temperature for 2 hours.
  • the reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, hexane / ethyl acetate), and 7- (ethylthio)-[1,3] dioxolo [4', 5': 5,6] benzo [1]. , 2-d] Thiazole was obtained (yield 0.26 g).
  • Example 2 Production of 1-([1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-yl) -5-phenylimidazolidine-2-one (First step) With 7- (ethylsulfonyl)-[1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole (0.3 g, 1.1 mmol) obtained in Reference Example 1. Using tert-butyl (2-amino-2-phenylethyl) carbamate (1 g, 4.4 mmol) obtained in the second step of Example 1, the method described in the third step of Example 1 was carried out in the same manner.
  • reaction solution was diluted with 2N aqueous sodium hydroxide solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure, and the crudely purified ((S) -2- ⁇ 2-[(7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) amino] -3-hydroxypropyl ⁇ was used. Isoindoline-1,3-dione was obtained (yield 0.7 g).
  • Example compounds [Table 1] are required according to the above-mentioned method described in Examples, using the corresponding raw materials (commercially available products or compounds derivatized from commercially available compounds by a known method or a method similar thereto). Therefore, it was produced by appropriately combining the methods usually used in synthetic organic chemistry.
  • the physicochemical data of each compound are shown in [Table 2].
  • Examples 23a, 23b, 24a, 24b, 25a, 25b, 49a, 49b, 55a, 55b, 58a, 58b, 59a, 59b, 83a and 83b are R-forms with respect to the substitution position of the substituent of the optically active center. Alternatively, it indicates that it is a stereoisomer of any of the S-forms. Further, these represent compounds obtained as a single compound by optical resolution.
  • A, B, and C indicate P / (P + S) of the blank well, P / (P + S) of the control solution well, and P / (P + S) of the compound-added well, respectively.
  • the IC50 value was calculated by regression analysis of the inhibition rate and the test compound concentration (logarithm). (Evaluation results) Table 3 shows the inhibitory activity of the representative compound of the present invention on DYRK1A, DYRK1B, DYRK2 and DYRK3. Kinase activity inhibitory effects are indicated by *** marks when the IC50 value is less than 0.01 ⁇ M, ** marks when 0.01 ⁇ M or more and less than 0.1 ⁇ M, * marks when 0.1 ⁇ M or more and less than 1 ⁇ M, and-when 1 ⁇ M or more. ..
  • test compound compound (I) of the present invention
  • compound (I) of the present invention has a strong DYRK inhibitory activity.
  • the compounds provided by the present invention are diseases known to be associated with DYRK1A-mediated abnormal cellular responses, such as Alzheimer's disease, Parkinson's disease, Down's disease, mental retardation, memory impairment, memory loss, depression. It is useful as a preventive or therapeutic agent for mental and neurological diseases such as, as well as cancers such as brain tumors. Further, as an inhibitor of DYRK1B, it is useful as a prophylactic or therapeutic drug (pharmaceutical composition) for cancers such as pancreatic cancer.
  • the compound provided by the present invention is useful as a prophylactic or therapeutic drug (pharmaceutical composition) for bone resorption disease and osteoporosis because it controls p53 in response to DNA damage and induces apoptosis of DYRK2.
  • the compound provided by the present invention is useful as an inhibitor of DYRK3 as a prophylactic or therapeutic drug (pharmaceutical composition) for sickle cell anemia, chronic kidney disease, bone resorption disease and osteoporosis.
  • a compound that inhibits DYRK it is useful as a reagent for pathological imagery related to the above-mentioned diseases and a reagent for basic experiments and research.

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Abstract

The present invention provides a compound that has an inhibitory effect on DYRK and is represented by general formula (I) (in the formula, A1, A2, L, R1, and R2 are as described in the specification).

Description

環状ウレア誘導体Cyclic urea derivative
　本発明は、医薬、特にＤＹＲＫ阻害作用を有する新規な環状ウレア誘導体またはその薬学的に許容される塩に関する。 The present invention relates to pharmaceuticals, in particular novel cyclic urea derivatives having DYRK inhibitory activity or pharmaceutically acceptable salts thereof.
　ＤＹＲＫ（Ｄｕａｌ－ｓｐｅｃｉｆｉｃｉｔｙ　ｔＹｒｏｓｉｎｅ－ｐｈｏｓｐｈｏｒｙｌａｔｉｏｎ　Ｒｅｇｕｌａｔｅｄ　ｐｒｏｔｅｉｎ　Ｋｉｎａｓｅ）は、チロシンおよびセリン、スレオニンをリン酸化する二重特異性プロテインキナーゼの一種である。ＤＹＲＫは、自己リン酸化の場合のみ、チロシンリン酸化酵素として機能し、外因性基質に対しては、セリンまたはスレオニン残基のリン酸化を触媒する。ＤＹＲＫファミリーのメンバーとして、ヒトでは、ＤＹＲＫ１Ａ、ＤＹＲＫ１Ｂ、ＤＹＲＫ２、ＤＹＲＫ３およびＤＹＲＫ４の５つが知られている（非特許文献１）。
　ＤＹＲＫ１Ａは、精神神経疾患との関連性が多く報告されている。例えば、アルツハイマー病患者では、βアミロイドの発現とＤＹＲＫ１Ａの発現とが有意に一致しており（非特許文献２）、さらにアルツハイマー病発症の一因とされるタウ・タンパク質（Ｔａｕ）の異常リン酸化に、ＤＹＲＫ１Ａが関与すると推測されている（非特許文献３）。
　また、パーキンソン病は、運動機能に重要なドーパミン神経が変性することによって引き起こされる神経変性疾患であるが、その原因の一つとして、ミトコンドリアの機能異常が考えられている（非特許文献４）。パーキンと呼ばれるタンパク質分解に関わる酵素は、異常ミトコンドリアを代謝し異常蓄積を抑える機能をもつことが知られているが、ＤＹＲＫ１Ａは、このパーキンタンパク質の活性を抑えることが報告されている（非特許文献５）。 DYRK (Dual-specificity tYrosine-phosphorylation regulated protein kinase) is a type of bispecific protein kinase that phosphorylates 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 to exogenous substrates. Five known members of the DYRK family, DYRK1A, DYRK1B, DYRK2, DYRK3 and DYRK4, are known in humans (Non-Patent Document 1).
DYRK1A has been widely reported to be associated with neuropsychiatric disorders. For example, in patients with Alzheimer's disease, β-amyloid expression and DYRK1A expression are significantly consistent (Non-Patent Document 2), and abnormal phosphorylation of tau protein (Tau), which is considered to contribute to the onset of Alzheimer's disease. It is presumed that DYRK1A is involved in this (Non-Patent Document 3).
Parkinson's disease is a neurodegenerative disease caused by degeneration of dopaminergic nerves, which are important for motor function, and one of the causes is considered to be mitochondrial dysfunction (Non-Patent Document 4). An enzyme involved in proteolysis called parkin is known to have a function of metabolizing abnormal mitochondria and suppressing abnormal accumulation, and DYRK1A has been reported to suppress the activity of this parkin protein (non-patent document). 5).
　ＤＹＲＫ１Ａの遺伝子は、ダウン症クリティカル領域に位置しており、ＤＹＲＫ１Ａの過剰発現したマウスでは、精神神経機能に異常をきたしダウン症様を示すことが報告されている（非特許文献６）。また、ダウン症患者およびダウン症様モデルマウスの脳内では、ＤＹＲＫ１Ａ発現が上昇していることが報告されている（非特許文献７）。これらのことは、ダウン症患者の神経症状の発症に、ＤＹＲＫ１Ａが関わっていることを示唆している（非特許文献８）。
　また、ダウン症患者では、若年性アルツハイマー病が多発することが報告されていることからも、ＤＹＲＫ１Ａがアルツハイマー病に密接に関係していることがわかる（非特許文献８）。
　したがって、ＤＹＲＫ１Ａを阻害する化合物は、アルツハイマー病、ダウン症、精神遅滞、記憶障害、記憶喪失およびパーキンソン病等の精神神経疾患の治療に有用であると考えられる。
　最近になって、ＤＹＲＫ１Ａがグリオブラストーマなどの脳腫瘍において高発現しており、ＤＹＲＫ１ＡがＥＧＦＲの発現を調節していることが報告されている（非特許文献９）。したがってＤＹＲＫ１Ａを阻害する化合物は、上皮成長因子受容体（ＥＧＦＲ）依存的な脳腫瘍や腫瘍などにおいて、がん細胞の増殖を抑制し、ＥＧＦＲ依存的ながんの治療に有用であると考えられる。 The gene for DYRK1A is located in the critical region of Down's syndrome, and it has been reported that mice overexpressing DYRK1A cause abnormalities in neuropsychiatric function and exhibit Down's syndrome (Non-Patent Document 6). In addition, it has been reported that DYRK1A expression is increased in the brains of Down's syndrome patients and Down's syndrome-like model mice (Non-Patent Document 7). These facts suggest that DYRK1A is involved in the onset of neurological symptoms in Down's syndrome patients (Non-Patent Document 8).
In addition, since it has been reported that juvenile Alzheimer's disease frequently occurs in Down's syndrome patients, it can be seen that DYRK1A is closely related to Alzheimer's disease (Non-Patent Document 8).
Therefore, compounds that inhibit DYRK1A are considered to be useful in the treatment of neuropsychiatric disorders such as Alzheimer's disease, Down's disease, mental retardation, memory impairment, memory loss and Parkinson's disease.
Recently, it has been reported that DYRK1A is highly expressed in brain tumors such as glioblastoma, and that DYRK1A regulates the expression of EGFR (Non-Patent Document 9). Therefore, the compound that inhibits DYRK1A is considered to be useful for the treatment of EGFR-dependent cancer by suppressing the growth of cancer cells in epidermal growth factor receptor (EGFR) -dependent brain tumors and tumors.
　また、ファミリー酵素である、ＤＹＲＫ１Ｂ、ＤＹＲＫ２およびＤＹＲＫ３を阻害する化合物に関しても、様々な医薬用途が考えられる。例えば、ＤＹＲＫ１Ｂは、休止期（Ｇ０期）のがん細胞において高発現し、各種の化学療法剤に対する抵抗性に寄与していることが報告されている（非特許文献１０）。ＤＹＲＫ１Ｂを阻害すると、Ｇ０期からの離脱を促進し、化学療法剤に対する感受性を向上させることも報告されている（非特許文献１１）。したがって、ＤＹＲＫ１Ｂを阻害する化合物は、膵臓がん、卵巣がん、骨肉腫、大腸がんや肺がんの治療に有用であると考えられる（非特許文献１１、１２、１３、１４、１５）。
　ＤＹＲＫ２については、ＤＮＡ損傷に応答してｐ５３を制御し、アポトーシスを誘導することが示唆されている（非特許文献１６）。さらに、ＤＹＲＫ３を阻害する化合物は、鎌状赤血球貧血および慢性腎疾患の治療に有用であることが報告されている（非特許文献１７）。
　ＤＹＲＫを阻害する化合物として特許文献１の他、ＤＹＲＫ１Ａ、ＤＹＲＫ１Ｂ阻害剤として特許文献２が報告されている。しかし、本発明の環状ウレア誘導体については記載されていない。 In addition, various pharmaceutical uses can be considered for compounds that inhibit the family enzymes DYRK1B, DYRK2 and DYRK3. For example, it has been reported that DYRK1B is highly expressed in telogen (G0 phase) cancer cells and contributes to resistance to various chemotherapeutic agents (Non-Patent Document 10). It has also been reported that inhibition of DYRK1B promotes withdrawal from the G0 phase and improves sensitivity to chemotherapeutic agents (Non-Patent Document 11). Therefore, the compound that inhibits DYRK1B is considered to be useful for the treatment of pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer and lung cancer (Non-Patent Documents 11, 12, 13, 14, 15).
It has been suggested that DYRK2 regulates p53 in response to DNA damage and induces apoptosis (Non-Patent Document 16). Furthermore, compounds that inhibit DYRK3 have been reported to be useful in the treatment of sickle cell anemia and chronic kidney disease (Non-Patent Document 17).
In addition to Patent Document 1 as a compound that inhibits DYRK, Patent Document 2 is reported as an inhibitor of DYRK1A and DYRK1B. However, the cyclic urea derivative of the present invention is not described.
ＷＯ２０１０／１０７９７号公報WO2010 / 10797 ＷＯ２０１３／２６８０６号公報WO2013 / 26806A
　本発明は、医薬、特にＤＹＲＫ阻害作用を有する新規化合物を提供することを課題とする。 An object of the present invention is to provide a pharmaceutical product, particularly a novel compound having a DYRK inhibitory effect.
本発明の目的は以下の（１）～（２３）によって達成される。
（１）下式（Ｉ）：
Figure JPOXMLDOC01-appb-C000003
 （式中、Ａ１は酸素原子、窒素原子（＝Ｎ－）またはＮＲＡを表し、
　Ａ２はＣＲＢ、ＣＲＣＲＤ、酸素原子、窒素原子（＝Ｎ－）またはＮＲＡを表し、
　ＲＡ、ＲＢ、ＲＣおよびＲＤは、それぞれ独立して、水素原子またはＣ１－６アルキル基を表し、
　Ｌはリンカーであって、炭素数１または２の炭素リンカー、窒素原子（＝Ｎ－）またはＮＲＡを表し、
　ここにおいて、Ａ１とＡ２はそれぞれ結合する芳香環およびリンカーＬと一緒になって、飽和もしくは不飽和の三環性縮合環を形成し、
　Ｒ1は、水素原子、置換基を有してもよいアルキル基、置換基を有してもよいアルケニル基、置換基を有してもよいシクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよい飽和複素環基を表し、
　Ｒ２は、水素原子またはメチル基を表す。）
で示される環状ウレア誘導体またはその薬学的に許容される塩； The object of the present invention is achieved by the following (1) to (23).
(1) The following formula (I):
Figure JPOXMLDOC01-appb-C000003
 (In the formula, A 1 represents an oxygen atom, a nitrogen atom (= N-) or NRA, and represents
A 2 represents CR B , CR C R D , oxygen atom, nitrogen atom (= N-) or NR A.
RA , RB, RC and RD each independently represent a hydrogen atom or a C 1-6 alkyl group.
L is a linker and represents a carbon linker having 1 or 2 carbon atoms, a nitrogen atom (= N−) or NRA .
Here, A 1 and A 2 together with the bonded aromatic ring and linker L form a saturated or unsaturated tricyclic condensed ring, respectively.
R 1 is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, and an aryl which may have a substituent. Represents a group, a heteroaryl group which may have a substituent, and a saturated heterocyclic group which may have a substituent.
R 2 represents a hydrogen atom or a methyl group. )
Cyclic urea derivative indicated by or a pharmaceutically acceptable salt thereof;
（２）Ａ１およびＡ２がいずれも酸素原子であり、Ｌが－（ＣＨ２）－である、上記（１）に記載の環状ウレア誘導体またはその薬学的に許容される塩；
（３）Ａ１が酸素原子であり、ＬおよびＡ２がいずれも－（ＣＨ２）－である、上記（１）に記載の環状ウレア誘導体またはその薬学的に許容される塩;
（４）Ｒ1が、水素原子、置換基を有してもよいＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ３－６シクロアルキル基、置換基を有してもよいフェニル基または置換基を有してもよいピリジル基を表す、上記（１）～（３）のいずれかに記載の環状ウレア誘導体またはその薬学的に許容される塩；
（５）Ｒ1が-ＣＨ２ＮＲ３Ｒ４または-ＣＨ２ＯＲ５で表され、
　Ｒ３、Ｒ４は、それぞれ独立して、水素原子、Ｃ１－６アルキル基（ヒドロキシ基でさらに置換されていてもよい）、Ｃ2－６アルキニル基、Ｃ2－６アルケニル基、Ｃ３－６シクロアルキル基、Ｃ１－６アシル基（ヒドロキシ基でさらに置換されていてもよい）、メタンスルホニル基またはシアノメチル基を表し、あるいは、Ｒ３とＲ４はそれらが結合する窒素原子と一緒になり、１～２個の酸素原子、硫黄原子（スルホキシド、スルホンを含む）、ケイ素原子またはリン原子を含んでもよい、置換基を有することのある、４員から１０員の単環性もしくは二環性の飽和環状アミノ基を形成してもよく、
　Ｒ５は、水素原子、Ｃ１－４アルキル基およびベンジル基から選択される、
上記（４）に記載の環状ウレア誘導体またはその薬学的に許容される塩；
（６）Ｒ1が置換基を有してもよいフェニル基または置換基を有してもよいピリジル基であり、当該置換基が、ハロゲン原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基である、
上記（４）に記載の環状ウレア誘導体またはその薬学的に許容される塩； (2) The cyclic urea derivative or a pharmaceutically acceptable salt thereof according to (1) above, wherein both A 1 and A 2 are oxygen atoms and L is-(CH 2 )-;
(3) The cyclic urea derivative or a pharmaceutically acceptable salt thereof according to (1) above, wherein A 1 is an oxygen atom and L and A 2 are both-(CH 2 )-;
(4) R 1 has a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, and a phenyl group which may have a substituent. Alternatively, the cyclic urea derivative according to any one of (1) to (3) above or a pharmaceutically acceptable salt thereof, which represents a pyridyl group which may have a substituent;
(5) R 1 is represented by -CH 2 NR 3 R 4 or -CH 2 OR 5 .
R 3 and R 4 are independently hydrogen atom, C 1-6 alkyl group (may be further substituted with hydroxy group), C 2-6 alkynyl group, C 2-6 alkenyl group, C 3 Represents a -6 cycloalkyl group, a C 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 together with the nitrogen atom to which they are attached. May contain 1 to 2 oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms, and may have substituents, 4 to 10 member monocyclic or two. A cyclic saturated cyclic amino group may be formed,
R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
The cyclic urea derivative according to (4) above or a pharmaceutically acceptable salt thereof;
(6) R 1 is a phenyl group which may have a substituent or a pyridyl group which may have a substituent, and the substituents are a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and the like. 1 to 3 substituents selected from the group consisting of hydroxymethyl groups,
The cyclic urea derivative according to (4) above or a pharmaceutically acceptable salt thereof;
（７）下式（Ｉ’）
Figure JPOXMLDOC01-appb-C000004
 〔式中、Ａ１、Ａ２、Ｌ、Ｒ１、Ｒ２は上記（Ｉ）に同じ〕
で示される上記（１）に記載の環状ウレア誘導体またはその薬学的に許容される塩;
（８）Ａ１およびＡ２がいずれも酸素原子であり、Ｌが－（ＣＨ２）－である、上記（７）に記載の環状ウレア誘導体またはその薬学的に許容される塩;
（９）Ａ１が酸素原子であり、ＬおよびＡ２がいずれも－（ＣＨ２）－である、上記（７）に記載の環状ウレア誘導体またはその薬学的に許容される塩；
（１０）Ｒ1が、水素原子、置換基を有してもよいＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ３－６シクロアルキル基、置換基を有してもよいフェニル基または置換基を有してもよいピリジル基を表す、上記（７）～（９）のいずれかに記載の環状ウレア誘導体またはその薬学的に許容される塩；
（１１）Ｒ1が、-ＣＨ２ＮＲ３Ｒ４または-ＣＨ２ＯＲ５で表され、
　Ｒ３、Ｒ４は、それぞれ独立して、水素原子、Ｃ１－６アルキル基（ヒドロキシ基でさらに置換されていてもよい）、Ｃ2－６アルキニル基、Ｃ2－６アルケニル基、Ｃ３－６シクロアルキル基、Ｃ１－６アシル基（ヒドロキシ基でさらに置換されていてもよい）、メタンスルホニル基またはシアノメチル基を表し、あるいは、Ｒ３とＲ４はそれらが結合する窒素原子と一緒になり、１～２個の酸素原子、硫黄原子（スルホキシド、スルホンを含む）、ケイ素原子またはリン原子を含んでもよい、置換基を有することのある、４員から１０員の単環性もしくは二環性の飽和環状アミノ基を形成してもよく、
　Ｒ５は、水素原子、Ｃ１－４アルキル基およびベンジル基から選択される、
上記（１０）に記載の環状ウレア誘導体またはその薬学的に許容される塩；
（１２）Ｒ1が置換基を有してもよいフェニル基または置換基を有してもよいピリジル基であり、当該置換基が、ハロゲン原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基である、上記（１０）に記載の環状ウレア誘導体またはその薬学的に許容される塩；および
（１３）Ｒ1が
１）水素原子、
２）シアノ基で置換されていてもよいＣ１－６アルキル基、
３）-ＣＨ２ＮＲ３Ｒ４または-ＣＨ２ＯＲ５で表され、
　Ｒ３、Ｒ４は、それぞれ独立して、水素原子、Ｃ１－６アルキル基（ヒドロキシ基でさらに置換されていてもよい）、Ｃ２－６アルケニル基、Ｃ３－６シクロアルキル基、Ｃ１－６アシル基（ヒドロキシ基でさらに置換されていてもよい）、メタンスルホニル基またはシアノメチル基を表し、あるいは、Ｒ３とＲ４はそれらが結合する窒素原子と一緒になり、１～２個の酸素原子、硫黄原子（スルホキシド、スルホンを含む）、ケイ素原子またはリン原子を含んでもよい、置換基を有することのある、５員から１０員の単環性もしくは二環性の飽和環状アミノ基を形成してもよく、該飽和環状アミノ基は、ハロゲン原子、オキソ基、メトキシ基、ヒドロキシ基、ヒドロキシメチル基、カルボキシ基、メトキシカルボニル基、ジメチルカルバモイル基、メチルカルバモイル基、およびジフルオロメチル基よりなる群から選択される１または２個の置換基で置換されていてもよく、
　Ｒ５は、水素原子、Ｃ１－４アルキル基およびベンジル基から選択され、
４）ハロゲン原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基で置換されていてもよいフェニル基、または
５）ハロゲン原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基で置換されていてもよいピリジル基、
である、請求項１または７に記載の環状ウレア誘導体またはその薬学的に許容される塩。
（１４）後記実施例１～２３０に記載された環状ウレア誘導体またはその薬学的に許容される塩。
（１５）上記（１）から（１４）のいずれか一項に記載の環状ウレア誘導体またはその薬学的に許容される塩を有効成分として含有する医薬。
（１６）上記（１）から（１４）のいずれか一項に記載の環状ウレア誘導体またはその薬学的に許容される塩を有効成分として含有する医薬組成物。
（１７）上記（１）から（１４）のいずれか一項に記載の環状ウレア誘導体またはその薬学的に許容される塩を有効成分として含有する、ＤＹＲＫが関与する疾患の治療剤及び／又は予防剤。
（１８）ＤＹＲＫが関与する疾患が、前頭側頭型認知症、進行性核上性麻痺、大脳皮質基底核変性症、レビー小体型認知症、血管性認知症、外傷性脳損傷、慢性外傷性脳症、脳卒中、アルツハイマー病、パーキンソン病、ダウン症、鬱病ならびにこれらに伴う精神遅滞、記憶障害、記憶喪失、学習障害、知的障害、認知機能障害、軽度認知障害、認知症症状あるいは脳腫瘍、膵臓がん、卵巣がん、骨肉腫、大腸がん、肺がん、骨吸収疾患、骨粗鬆症鎌状赤血球貧血、慢性腎疾患または骨吸収疾患である、上記（１７）に記載の治療剤及び／又は予防剤。
（１９）治療が必要な患者に、治療上の有効量の上記（１）から（１４）のいずれか一項に記載の化合物、又はその製薬学的に許容される塩を投与することを含む、ＤＹＲＫが関与する疾患を治療及び／又は予防するための方法。
（２０）ＤＹＲＫが関与する疾患の治療剤及び／又は予防剤を製造するための、上記（１）から（１４）のいずれか一項に記載の環状ウレア誘導体、又はその製薬学的に許容される塩の使用。
（２１）ＤＹＲＫが関与する疾患の治療及び／又は予防に使用するための、上記（１）から（１４）のいずれか一項に記載の環状ウレア誘導体、又はその製薬学的に許容される塩。
（２２）上記（１５）に記載の医薬と、抗がん剤、抗精神病薬、抗認知症薬、抗てんかん薬、抗うつ薬、胃腸薬、甲状腺ホルモン薬又は抗甲状腺薬に分類される薬剤から選択される少なくとも１種以上の薬剤とを組み合わせてなる医薬。
（２３）抗がん剤、抗精神病薬、抗認知症薬、抗てんかん薬、抗うつ薬、胃腸薬、甲状腺ホルモン薬又は抗甲状腺薬に分類される薬剤から選択される少なくとも１種以上の薬剤と併用して前頭側頭型認知症、進行性核上性麻痺、大脳皮質基底核変性症、レビー小体型認知症、血管性認知症、外傷性脳損傷、慢性外傷性脳症、脳卒中、アルツハイマー病、パーキンソン病、ダウン症、鬱病ならびにこれらに伴う合併症、精神遅滞、記憶障害、記憶喪失、学習障害、知的障害、認知機能障害、軽度認知障害、認知症症状あるいは脳腫瘍、膵臓がん、卵巣がん、骨肉腫、大腸がん、肺がん、骨吸収疾患、骨粗鬆症、鎌状赤血球貧血、慢性腎疾患または骨吸収疾患を治療するための、上記（１５）に記載の医薬。 (7) The following formula (I')
Figure JPOXMLDOC01-appb-C000004
 [In the formula, A 1 , A 2 , L, R 1 , and R 2 are the same as (I) above]
The cyclic urea derivative according to (1) above or a pharmaceutically acceptable salt thereof;
(8) The cyclic urea derivative or a pharmaceutically acceptable salt thereof according to (7) above, wherein both A 1 and A 2 are oxygen atoms and L is-(CH 2 )-;
(9) The cyclic urea derivative or a pharmaceutically acceptable salt thereof according to (7) above, wherein A 1 is an oxygen atom and L and A 2 are both-(CH 2 )-;
(10) R 1 has a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, and a phenyl group which may have a substituent. Alternatively, the cyclic urea derivative according to any one of (7) to (9) above or a pharmaceutically acceptable salt thereof, which represents a pyridyl group which may have a substituent;
(11) R 1 is represented by -CH 2 NR 3 R 4 or -CH 2 OR 5 .
R 3 and R 4 are independently hydrogen atom, C 1-6 alkyl group (may be further substituted with hydroxy group), C 2-6 alkynyl group, C 2-6 alkenyl group, C 3 Represents a -6 cycloalkyl group, a C 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 together with the nitrogen atom to which they are attached. May contain 1 to 2 oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms, and may have substituents, 4 to 10 member monocyclic or two. A cyclic saturated cyclic amino group may be formed,
R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
The cyclic urea derivative according to (10) above or a pharmaceutically acceptable salt thereof;
(12) R 1 is a phenyl group which may have a substituent or a pyridyl group which may have a substituent, and the substituents are a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and the like. The cyclic urea derivative or pharmaceutically acceptable salt thereof according to (10) above, which is 1 to 3 substituents selected from the group consisting of hydroxymethyl groups; and (13) R 1 is 1) hydrogen. atom,
2) C 1-6 alkyl group, which may be substituted with a cyano group,
3) Represented by -CH 2 NR 3 R 4 or -CH 2 OR 5
Independently, R 3 and R 4 are a hydrogen atom, a C 1-6 alkyl group (which may be further substituted with a hydroxy group), a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, and a C. Representing a 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 are combined with the nitrogen atom to which they are attached, 1-2. 5- to 10-membered monocyclic or bicyclic saturated cyclic amino groups, which may contain substituents, may contain oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms. The saturated cyclic amino group may be composed of a halogen atom, an oxo group, a methoxy group, a hydroxy group, a hydroxymethyl group, a carboxy group, a methoxycarbonyl group, a dimethylcarbamoyl group, a methylcarbamoyl group, and a difluoromethyl group. May be substituted with one or two substituents selected from the group of
R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
4) A phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and a hydroxymethyl group, or 5) a halogen atom, A pyridyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a vinyl group, a methoxy group, a cyano group, a hydroxy group and a hydroxymethyl group.
The cyclic urea derivative according to claim 1 or 7, or a pharmaceutically acceptable salt thereof.
(14) The cyclic urea derivative or a pharmaceutically acceptable salt thereof according to Examples 1 to 230 described later.
(15) A drug containing the cyclic urea derivative according to any one of (1) to (14) above or a pharmaceutically acceptable salt thereof as an active ingredient.
(16) A pharmaceutical composition containing the cyclic urea derivative according to any one of (1) to (14) above or a pharmaceutically acceptable salt thereof as an active ingredient.
(17) A therapeutic agent and / or prevention of a disease associated with DYRK containing the cyclic urea derivative according to any one of (1) to (14) above or a pharmaceutically acceptable salt thereof as an active ingredient. Agent.
(18) Diseases associated with DYRK are frontotemporal dementia, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, Levy body dementia, vascular dementia, traumatic brain injury, chronic traumatic Encephalopathy, stroke, Alzheimer's disease, Parkinson's disease, Down's disease, depression and associated mental retardation, memory impairment, memory loss, learning impairment, intellectual disability, cognitive dysfunction, mild cognitive impairment, dementia symptoms or brain tumor, pancreatic cancer , Ovarian cancer, osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis sickle red erythrocyte anemia, chronic renal disease or bone resorption disease, the therapeutic agent and / or the prophylactic agent according to (17) above.
(19) The present invention comprises administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of (1) to (14) above, or a pharmaceutically acceptable salt thereof. , A method for treating and / or preventing a disease involving DYRK.
(20) The cyclic urea derivative according to any one of (1) to (14) above, or pharmaceutically acceptable thereof, for producing a therapeutic agent and / or a preventive agent for a disease involving DYRK. Use of salt.
(21) The cyclic urea derivative according to any one of (1) to (14) above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of diseases associated with DYRK. ..
(22) The drug according to (15) above, and a drug classified into an anticancer drug, an antipsychotic drug, an antidepressant drug, an antiepileptic drug, an antidepressant drug, a gastrointestinal drug, a thyroid hormone drug or an antithyroid drug. A drug consisting of a combination of at least one drug selected from the above.
(23) At least one drug selected from drugs classified into anticancer drugs, antipsychotic drugs, dementia drugs, antiepileptic drugs, antidepressants, gastrointestinal drugs, thyroid hormone drugs or antithyroid drugs. In combination with frontotemporal dementia, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, Levy body dementia, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, stroke, Alzheimer's disease , Parkinson's disease, Down's disease, depression and related complications, mental retardation, memory disorder, memory loss, learning disorder, intellectual disorder, cognitive dysfunction, mild cognitive disorder, dementia symptoms or brain tumor, pancreatic cancer, ovary The pharmaceutical according to (15) above for treating sickness, osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis, sickle red erythrocyte anemia, chronic renal disease or bone resorption disease.
　本発明者らは、上記の課題を解決するために種々検討を重ねた結果、前記式（Ｉ）で示される新規環状ウレア誘導体およびその薬学的に許容される塩が、優れたＤＹＲＫ阻害作用を有することを見出し、本発明を完成させた。本発明により提供される化合物は、ＤＹＲＫ１Ａを介した異常な細胞応答に関連していることが知られている疾患、例えば、アルツハイマー病、パーキンソン病、ダウン症、鬱病のような精神・神経疾患、ならびにこれらに伴う精神遅滞、記憶障害、記憶喪失、学習障害、知的障害、認知機能障害、軽度認知障害、認知症症状進行の治療薬又は認知症発症の予防薬、さらに脳腫瘍などの腫瘍に対する予防または治療用医薬品（医薬組成物）として有用である。本発明により提供される化合物は、ＤＹＲＫ１Ｂの阻害剤として、膵臓がん、卵巣がん、骨肉腫、大腸がん、肺がんなどの腫瘍に対する予防または治療用医薬品（医薬組成物）として有用である。さらに本発明により提供される化合物は、ＤＹＲＫ２について、ＤＮＡ損傷に応答してｐ５３を制御し、アポトーシスを誘導することから、骨吸収疾患および骨粗鬆症に対する予防または治療用医薬品（医薬組成物）として有用である。また本発明により提供される化合物は、ＤＹＲＫ３の阻害剤として、鎌状赤血球貧血、慢性腎疾患、骨吸収疾患および骨粗鬆症に対する予防または治療用医薬品（医薬組成物）として有用である。また、ＤＹＲＫを阻害する化合物として、上記の疾患に関する病態イメージングの試薬や基礎実験用、研究用の試薬に有用である。 As a result of various studies to solve the above problems, the present inventors have found that the novel cyclic urea derivative represented by the above formula (I) and the pharmaceutically acceptable salt thereof have an excellent DYRK inhibitory effect. It was found to have, and the present invention was completed. The compounds provided by the present invention include diseases known to be associated with DYRK1A-mediated aberrant cellular responses, such as mental and neurological disorders such as Alzheimer's disease, Parkinson's disease, Down's disease, depression, as well. Mental retardation, memory impairment, memory loss, learning disability, intellectual disability, cognitive dysfunction, mild cognitive impairment, dementia symptom progression therapeutic agent or dementia onset preventive agent, and prevention or prevention of tumors such as brain tumors It is useful as a therapeutic drug (pharmaceutical composition). The compound provided by the present invention is useful as an inhibitor of DYRK1B as a prophylactic or therapeutic drug (pharmaceutical composition) for tumors such as pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer, and lung cancer. Furthermore, the compound provided by the present invention is useful as a prophylactic or therapeutic drug (pharmaceutical composition) for bone resorption disease and osteoporosis because it controls p53 in response to DNA damage and induces apoptosis of DYRK2. be. Further, the compound provided by the present invention is useful as an inhibitor of DYRK3 as a prophylactic or therapeutic drug (pharmaceutical composition) for sickle cell anemia, chronic kidney disease, bone resorption disease and osteoporosis. Further, as a compound that inhibits DYRK, it is useful as a reagent for pathological imagery related to the above-mentioned diseases and a reagent for basic experiments and research.
　以下、本発明を詳細に説明する。
　本発明の新規な環状ウレア誘導体は、下式（Ｉ）：
Figure JPOXMLDOC01-appb-C000005
 （式中、Ａ１は酸素原子、窒素原子（＝Ｎ－）またはＮＲＡを表し、
　Ａ２はＣＲＢ、ＣＲＣＲＤ、酸素原子、窒素原子（＝Ｎ－）またはＮＲＡを表し、
　ＲＡ、ＲＢ、ＲＣおよびＲＤは、それぞれ独立して、水素原子またはＣ１－６アルキル基を表し、
　Ｌはリンカーであって、炭素数１または２の炭素リンカー、窒素原子（＝Ｎ－）またはＮＲＡを表し、
　ここにおいて、Ａ１とＡ２はそれぞれ結合する芳香環およびリンカーＬと一緒になって、飽和もしくは不飽和の三環性縮合環を形成し、
Ｒ1は、水素原子、置換基を有してもよいアルキル基、置換基を有してもよいアルケニル基、置換基を有してもよいシクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよい飽和複素環基を表し、
　Ｒ２は、水素原子またはメチル基を表す。）
で示される化合物である。 Hereinafter, the present invention will be described in detail.
The novel cyclic urea derivative of the present invention has the following formula (I):
Figure JPOXMLDOC01-appb-C000005
 (In the formula, A 1 represents an oxygen atom, a nitrogen atom (= N-) or NRA, and represents
A 2 represents CR B , CR C R D , oxygen atom, nitrogen atom (= N-) or NR A.
RA , RB, RC and RD each independently represent a hydrogen atom or a C 1-6 alkyl group.
L is a linker and represents a carbon linker having 1 or 2 carbon atoms, a nitrogen atom (= N−) or NRA .
Here, A 1 and A 2 together with the bonded aromatic ring and linker L form a saturated or unsaturated tricyclic condensed ring, respectively.
R 1 is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, and an aryl which may have a substituent. Represents a group, a heteroaryl group which may have a substituent, and a saturated heterocyclic group which may have a substituent.
R 2 represents a hydrogen atom or a methyl group. )
It is a compound indicated by.
　前記式（Ｉ）において、Ａ１とＡ２およびリンカーＬを含んで構成される環部分としては、窒素原子および酸素原子から選ばれる少なくとも１個のヘテロ原子を含み、置換基を有していてもよい飽和または不飽和のヘテロ５員環またはヘテロ６員環が例示される。そして、Ｌは、炭素数１または２の炭素リンカー、窒素原子（＝Ｎ－）またはＮＲＡであり、炭素数１から２の炭素リンカーとは、メチン、メチレン、エチレン、ビニレン、エタンジイリデン等が例示され、エチレンはいずれかの炭素がオキソ基で置換されていてもよい。また、ＲＡとしては、水素原子またはメチル基が例示される。
　また、当該Ａ１とＡ２およびリンカーＬを含んで構成される環部分としては、ベンゾチアゾール環と縮合して、例えばジヒドロベンゾフロチアゾール、ジオキソロベンゾチアゾール、キノリノチアゾール、キノキサリノチアゾール、イミダゾベンゾチアゾール、チアゾロインダゾール、チアゾロベンゾオキサゾール、チアゾロベンゾオキサジン、チアゾロベンゾオキサジンオン、などの三環性縮合環が例示される。
　Ａ１が酸素原子の場合、リンカーＬがメチレンでＡ２が酸素原子またはＣＲCＲＤが好ましく、特にＲＣ、ＲＤは水素原子が好ましい。
　また、Ａ１が酸素原子の場合、リンカーＬがエチレンでＡ２がＮＲＡも好ましく、特にＲＡはＣ１－６アルキル、中でもメチルが好ましい。
　Ａ１が窒素原子の場合、リンカーＬが窒素原子またはメチンであってＡ２はＮＲＡが好ましく、この場合ＲＡはメチルが好ましい。
　また、Ａ１が窒素原子の場合、リンカーＬがエタンジイリデンであってＡ２がＮＲＡもしくはＣＲＢも好ましく、この場合、ＲＡは水素原子、ＲＢはメチルが好ましい。 In the formula (I), the ring portion composed of A 1 , A 2 and the linker L contains at least one hetero atom selected from a nitrogen atom and an oxygen atom, and has a substituent. A good saturated or unsaturated hetero 5-membered or hetero 6-membered ring is exemplified. L is a carbon linker having 1 or 2 carbon atoms, a nitrogen atom (= N-) or NR A , and examples of the carbon linkers having 1 to 2 carbon atoms include methine, methylene, ethylene, vinylene and ethanediylidene. In ethylene, any carbon may be substituted with an oxo group. Further, as RA , a hydrogen atom or a methyl group is exemplified.
Further, the ring portion composed of A 1 and A 2 and the linker L is condensed with a benzothiazole ring and, for example, dihydrobenzoflotiazole, dioxolobenzothiazole, quinolinothiazole, quinoxalinothiazole. , Imidazobenzothiazole, thiazoloinazole, thiazolobenzoxazole, thiazolobenzoxazine, thiazolobenzoxazineone, and the like are exemplified.
When A 1 is an oxygen atom, the linker L is preferably methylene, A 2 is preferably an oxygen atom or CR CRD , and RC and R D are particularly preferably hydrogen atoms.
When A 1 is an oxygen atom, the linker L is preferably ethylene and A 2 is preferably NR A , and RA is particularly preferably C 1-6 alkyl, particularly methyl.
When A 1 is a nitrogen atom, the linker L is a nitrogen atom or methine, and A 2 is preferably NR A , in which case RA is preferably methyl.
When A 1 is a nitrogen atom, linker L is preferably ethandylidene and A 2 is preferably NRA or CR B. In this case, RA is preferably a hydrogen atom and RB is preferably methyl.
　「ＤＹＲＫ」とは、Ｄｕａｌ－ｓｐｅｃｉｆｉｃｉｔｙ　ｔＹｒｏｓｉｎｅ－ｐｈｏｓｐｈｏｒｙｌａｔｉｏｎ　Ｒｅｇｕｌａｔｅｄ　ｐｒｏｔｅｉｎ　Ｋｉｎａｓｅを表し、ＤＹＲＫファミリー（ＤＹＲＫ１Ａ，ＤＹＲＫ１Ｂ、ＤＹＲＫ２、ＤＹＲＫ３、ＤＹＲＫ４）の一または二以上を意味する。 "DYRK" represents Dual-specificity tYrosine-phosphorylated protein kinase, and means one of the DYRK family (DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4 or more).
　置換基を有してもよいアルキル基としては、例えば炭素数１から６の直鎖状または分枝状のアルキル基（Ｃ１－６アルキル基）などが挙げられ、具体的には、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｔｅｒｔ-ブチル基などが挙げられる。
　同様に、Ｃ１－４アルキル基は、炭素数１から４の直鎖状または分枝状のアルキル基を表す。
　置換基を有してもよいアルケニル基としては、例えば炭素数２から６の直鎖状または分枝状のアルケニル基（Ｃ２－６アルケニル基）などが挙げられ、具体的には、ビニル基、アリル基、１－プロペニル基、イソプロペニル基、２－メチルアリル基などが挙げられる。
　置換基を有してもよいアルキニル基としては、例えば炭素数２から６の直鎖状または分枝状のアルキニル基（Ｃ２－６アルキニル基）などが挙げられ、具体的には、エチニル基、２－プロピニル基、２－ブチニル基などが挙げられる。
　置換基を有してもよいシクロアルキル基としては、例えば炭素数３から６のシクロアルキル基（Ｃ３－６シクロアルキル基）が例示され、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基などが挙げられる。
　置換基を有してもよいアリール基としては、例えば炭素数６から１４のアリール基などが挙げられ、具体的には、フェニル基などが挙げられる。
　置換基を有してもよいヘテロアリール基としては、例えば、窒素原子、硫黄原子および酸素原子から選ばれる少なくとも１個のヘテロ原子を含む５または６員のヘテロアリール基などが挙げられ、具体的には、チエニル基、フリル基、ピロール基、ピリジル基などが挙げられるが、ピリジル基が最も好ましい。
　置換基を有してもよい飽和複素環基としては、例えば、窒素原子、硫黄原子および酸素原子から選ばれる少なくとも１個のヘテロ原子を含む４から６員の単環性飽和複素環基などが挙げられ、具体的には、アゼチジニル基、ピロリジニル基、ピぺリジニル基、オキセタニル基、テトラヒドロフラニル基、テトラヒドロピラニル基などが挙げられる。 Examples of the alkyl group which may have a substituent include a linear or branched alkyl group having 1 to 6 carbon atoms (C 1-6 alkyl group), and specifically, a methyl group. , Ethyl group, n-propyl group, isopropyl group, tert-butyl group and the like.
Similarly, the C 1-4 alkyl group represents a linear or branched alkyl group having 1 to 4 carbon atoms.
Examples of the alkenyl group which may have a substituent include a linear or branched alkenyl group having 2 to 6 carbon atoms (C 2-6 alkenyl group), and specifically, a vinyl group. , Allyl group, 1-propenyl group, isopropenyl group, 2-methylallyl group and the like.
Examples of the alkynyl group which may have a substituent include a linear or branched alkynyl group having 2 to 6 carbon atoms (C 2-6 alkynyl group), and specifically, an ethynyl group. , 2-Propinyl group, 2-Butynyl group and the like.
Examples of the cycloalkyl group which may have a substituent include a cycloalkyl group having 3 to 6 carbon atoms (C 3-6 cycloalkyl group), for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. And so on.
Examples of the aryl group which may have a substituent include an aryl group having 6 to 14 carbon atoms, and specific examples thereof include a phenyl group.
Specific examples of the heteroaryl group which may have a substituent include a 5- or 6-membered heteroaryl group containing at least one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom. Examples thereof include a thienyl group, a frill group, a pyrrol group, a pyridyl group and the like, and the pyridyl group is most preferable.
Examples of the saturated heterocyclic group which may have a substituent include a 4- to 6-membered monocyclic saturated heterocyclic group containing at least one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom. Specific examples thereof include an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group and the like.
　置換基を有してもよいアルキル基、置換基を有してもよいアルケニル基および置換基を有してもよいシクロアルキル基の「置換基」としては、特に記載のない限り、１または２個以上の任意の種類の置換基を、化学的に可能な任意の位置に有してもよく、置換基が２個以上の場合、それぞれの置換基は同一であっても異なっていてもよい。置換基の具体例としては、Ｃ３－６シクロアルキル基、ハロゲン原子、Ｃ１－４アルコキシ基、シアノ基、ベンジルオキシ基、フェニル基、ヒドロキシ基、メタンスルホニル基、－ＮＲ３Ｒ４で表される置換もしくは非置換アミノ基が例示される。 Unless otherwise specified, the "substituent" of the alkyl group which may have a substituent, the alkenyl group which may have a substituent and the cycloalkyl group which may have a substituent may be 1 or 2. Any kind of substituents of any kind may be present at any position chemically possible, and when there are two or more substituents, the substituents may be the same or different. .. Specific examples of the substituent are represented by C 3-6 cycloalkyl group, halogen atom, C 1-4 alkoxy group, cyano group, benzyloxy group, phenyl group, hydroxy group, methanesulfonyl group and -NR 3 R 4 . The substituted or unsubstituted amino group to be substituted is exemplified.
　Ｒ1の定義中、置換基を有してもよいアルキル基は、また、-ＣＨ２ＮＲ３Ｒ４または-ＣＨ２ＯＲ５で表すこともできる。
　この場合、Ｒ３、Ｒ４は、それぞれ独立して、水素原子、Ｃ１－６アルキル基（例えばメチル基）、Ｃ２－６アルケニル基（例えばビニル基、アリル基）、Ｃ２－６アルキニル基（例えば、２－プロピニル基、２－ブチニル基）、Ｃ３－６シクロアルキル基（例えばシクロプロピル基）、Ｃ１－６アシル基（例えばアセチル基、プロピオニル基、ブチリル基）、メタンスルホニル基等を表し、Ｃ１－６アルキル基は、ヒドロキシ基、フェニル基、シアノ基、ハロフェニル基などでさらに置換されていてもよい。また、Ｃ１－６アシル基はヒドロキシ基で置換されていてもよい。さらに、Ｒ３とＲ４はそれらが結合する窒素原子と一緒になり、１～２個の酸素原子、硫黄原子（スルホキシド、スルホンを含む）、ケイ素原子またはリン原子を含んでもよい、置換基を有することのある、４員から１０員の単環性もしくは二環性の飽和環状アミノ基を構成する。該飽和環状アミノ基の具体例としては、アゼチニジル基、ピロリジニル基、ピペラジニル基、ホモピペリジニル基、モルホリニル基、１，４－オキサゼパニル基、チオモルホリニル基等の単環性環状アミノ基；（テトラヒドロ－１Ｈ－フロ［３，４－ｃ］ピロール－５（３Ｈ）－イル）基、（２－オキサ－７－アザスピロ［４．４］ノナン－７－イル）基、（８－オキサ－３－アザビシクロ［３．２．１］オクタン－３－イル）基、（５－オキサ－８－アザスピロ［３．５］ノナン－８－イル）基、（２－オキサ－５－アザビシクロ［２．２．１］ヘプタン－５－イル）基、（６－オキサ－１－アザスピロ［３．３］ヘプタン－１－イル）基、（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）基等の二環性環状アミノ基が挙げられ、これら環状アミノ基は、ハロゲン原子、メチル基、オキソ基、メトキシ基、ヒドロキシ基、ヒドロキシメチル基、ヒドロキシイソプロピル基、カルボキシ基、メトキシカルボニル基、ジメチルカルバモイル基、メチルカルバモイル基およびジフルオロメチル基よりなる群から選択される、１～３個の置換基で置換されていてもよい。
　Ｒ５は、水素原子、Ｃ１－４アルキル基およびベンジル基から選択される。
　置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよい飽和複素環基の「置換基」としては、特に記載のない限り、１または２個以上の任意の種類の置換基を、化学的に可能な任意の位置に有してもよく、置換基が２個以上の場合、それぞれの置換基は同一であっても異なっていてもよい。置換基の具体例としては、ハロゲン原子、ビニル基、メチル基、メトキシ基、シアノ基、ヒドロキシ基、ヒドロキシメチル基等が例示される。 In the definition of R 1 , the alkyl group which may have a substituent can also be represented by -CH 2 NR 3 R 4 or -CH 2 OR 5 .
In this case, R 3 and R 4 are independently hydrogen atom, C 1-6 alkyl group (for example, methyl group), C 2-6 alkenyl group (for example, vinyl group, allyl group), C 2-6 alkynyl. Group (eg 2-propynyl group, 2-butynyl group), C 3-6 cycloalkyl group (eg cyclopropyl group), C 1-6 acyl group (eg acetyl group, propionyl group, butyryl group), methanesulfonyl group The C 1-6 alkyl group may be further substituted with a hydroxy group, a phenyl group, a cyano group, a halophenyl group or the like. Further, the C 1-6 acyl group may be substituted with a hydroxy group. In addition, R 3 and R 4 combine with the nitrogen atom to which they bind and may contain one or two oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms, substituents. It constitutes a 4- to 10-membered monocyclic or bicyclic saturated cyclic amino group that may have. Specific examples of the saturated cyclic amino group include monocyclic cyclic amino groups such as azetinidyl group, pyrrolidinyl group, piperazinyl group, homopiperidinyl group, morpholinyl group, 1,4-oxazepanyl group and thiomorpholinyl group; (tetrahydro-1H-flow). [3,4-c] pyrrol-5 (3H) -yl) group, (2-oxa-7-azaspiro [4.4] nonan-7-yl) group, (8-oxa-3-azabicyclo [3. 2.1] Octane-3-yl) group, (5-oxa-8-azaspiro [3.5] nonane-8-yl) group, (2-oxa-5-azabicyclo [2.2.1] heptane- 5-yl) group, (6-oxa-1-azaspiro [3.3] heptane-1-yl) group, (1,4-dioxa-8-azaspiro [4.5] decane-8-yl) group, etc. Bicyclic amino groups include halogen atoms, methyl groups, oxo groups, methoxy groups, hydroxy groups, hydroxymethyl groups, hydroxyisopropyl groups, carboxy groups, methoxycarbonyl groups and dimethylcarbamoyl groups. , Methylcarbamoyl group and difluoromethyl group may be substituted with 1 to 3 substituents selected from the group.
R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
Unless otherwise specified, the "substituted group" of the aryl group which may have a substituent, the heteroaryl group which may have a substituent, and the saturated heterocyclic group which may have a substituent is 1 Alternatively, two or more of any kind of substituents may be present at any chemically possible position, and when there are two or more substituents, the respective substituents may be the same but different. May be good. Specific examples of the substituent include a halogen atom, a vinyl group, a methyl group, a methoxy group, a cyano group, a hydroxy group, a hydroxymethyl group and the like.
　本発明の新規な環状ウレア体（Ｉ）においては、次の態様が好ましい。
　すなわち、置換基Ｒ１が、
１）水素原子、
２）シアノ基で置換されていてもよいＣ１－６アルキル基、
３）-ＣＨ２ＮＲ３Ｒ４または-ＣＨ２ＯＲ５で表され、
　Ｒ３、Ｒ４は、それぞれ独立して、水素原子、Ｃ１－６アルキル基（ヒドロキシ基でさらに置換されていてもよい）、Ｃ２－６アルケニル基、Ｃ３－６シクロアルキル基、Ｃ１－６アシル基（ヒドロキシ基でさらに置換されていてもよい）、メタンスルホニル基またはシアノメチル基を表し、あるいは、Ｒ３とＲ４はそれらが結合する窒素原子と一緒になり、１～２個の酸素原子、硫黄原子（スルホキシド、スルホンを含む）、ケイ素原子またはリン原子を含んでもよい、置換基を有することのある、５員から１０員の単環性もしくは二環性の飽和環状アミノ基を形成してもよく、該飽和環状アミノ基は、ハロゲン原子、オキソ基、メトキシ基、ヒドロキシ基、ヒドロキシメチル基、カルボキシ基、メトキシカルボニル基、ジメチルカルバモイル基、メチルカルバモイル基、およびジフルオロメチル基よりなる群から選択される１または２個の置換基で置換されていてもよく、
　Ｒ５は、水素原子、Ｃ１－４アルキル基およびベンジル基から選択され、
４）ハロゲン原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基で置換されていてもよいフェニル基、または
５）ハロゲン原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基で置換されていてもよいピリジル基、
である、環状ウレア誘導体（Ｉ）またはその薬学的に許容される塩が好ましい。 In the novel cyclic urea form (I) of the present invention, the following aspects are preferable.
That is, the substituent R 1 is
1) Hydrogen atom,
2) C 1-6 alkyl group, which may be substituted with a cyano group,
3) Represented by -CH 2 NR 3 R 4 or -CH 2 OR 5
Independently, R 3 and R 4 are a hydrogen atom, a C 1-6 alkyl group (which may be further substituted with a hydroxy group), a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, and a C. Representing a 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 are combined with the nitrogen atom to which they are attached, 1-2. 5- to 10-membered monocyclic or bicyclic saturated cyclic amino groups, which may contain substituents, may contain oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms. The saturated cyclic amino group may be composed of a halogen atom, an oxo group, a methoxy group, a hydroxy group, a hydroxymethyl group, a carboxy group, a methoxycarbonyl group, a dimethylcarbamoyl group, a methylcarbamoyl group, and a difluoromethyl group. May be substituted with one or two substituents selected from the group of
R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
4) A phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and a hydroxymethyl group, or 5) a halogen atom, A pyridyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a vinyl group, a methoxy group, a cyano group, a hydroxy group and a hydroxymethyl group.
The cyclic urea derivative (I) or a pharmaceutically acceptable salt thereof is preferred.
　本願明細書では、ハロゲン原子としては、Ｃｌ、Ｂｒ、ＦおよびＩが該当し、特にＣｌ、Ｂｒ、Ｆが好ましい。
　また、本発明の化合物（Ｉ）の薬学的に許容される塩としては、塩酸、硫酸、炭酸、リン酸等との無機酸塩、フマル酸、マレイン酸、メタンスルホン酸、ｐ－トルエンスルホン酸等との有機酸塩等が挙げられる。また、ナトリウム、カリウム等とのアルカリ金属塩、マグネシウム、カルシウム等とのアルカリ土類金属塩、低級アルキルアミン、低級アルコールアミン等との有機アミン塩、リジン、アルギニン、オルニチン等との塩基性アミノ酸塩の他、アンモニウム塩等も本発明に包含される。
　本発明の化合物（Ｉ）は、例えば、置換基の種類によって、異性体が存在する場合がある。本明細書において、それらの異性体の一形態のみの化学構造で記載することがあるが、本発明には、構造上生じ得るすべての異性体（幾何異性体、立体異性体、互変異性体など）も包含され、異性体単体、またはそれらの混合物もすべて包含される。
　本発明の化合物（Ｉ）およびその薬学的に許容される塩は、たとえば以下の方法によって製造することができる。なお、以下に示した製造法において、定義した基が実施方法の条件下で変化するか、または方法を実施するのに不適切な場合、有機合成化学で通常用いられる方法、例えば、官能基の保護、脱保護［Ｔ．Ｗ．Ｇｒｅｅｎｅ、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ ３ｒｄ Ｅｄｉｔｉｏｎ、Ｊｏｈｎ Ｗｉｌｅｙ ＆Ｓｏｎｓ、ｌｎｃ．、１９９９］などの手段を付すことにより容易に製造することができる。また、必要に応じて置換基導入などの反応工程の順序を変えることもできる。 In the present specification, Cl, Br, F and I correspond to the halogen atom, and Cl, Br, F are particularly preferable.
The pharmaceutically acceptable salts of the compound (I) of the present invention include inorganic acid salts with hydrochloric acid, sulfuric acid, carbonic acid, phosphoric acid and the like, fumaric acid, maleic acid, methanesulfonic acid and p-toluenesulfonic acid. And the like, organic acid salts and the like can be mentioned. Also, alkali metal salts with sodium, potassium, etc., alkaline earth metal salts with magnesium, calcium, etc., organic amine salts with lower alkylamines, lower alcohol amines, etc., basic amino acid salts with lysine, arginine, ornithine, etc. In addition, ammonium salts and the like are also included in the present invention.
The compound (I) of the present invention may have an isomer, for example, depending on the type of substituent. In the present specification, only one form of these isomers may be described as a chemical structure, but in the present invention, all isomers (geometric isomers, steric isomers, remutable isomers) that may occur structurally are described. Etc.) are also included, including single isomers or all mixtures thereof.
The compound (I) of the present invention and a pharmaceutically acceptable salt thereof can be produced, for example, by the following method. In the production method shown below, if the defined group changes under the conditions of the method or is inappropriate for carrying out the method, a method usually used in synthetic organic chemistry, for example, a functional group. Protection, deprotection [T. W. Greene, Protective Groups in Organic Synthesis 3rd Edition, John Wiley & Sons, lnc. , 1999] and the like, it can be easily manufactured. In addition, the order of reaction steps such as introduction of substituents can be changed as needed.
　以下の説明で使用される略語、記号の意味は次の通りである。
ＤＣＭ ： ジクロロメタン
ＴＨＦ ： テトラヒドロフラン
ＤＭＦ ： Ｎ，Ｎ－ジメチルホルムアミド
ＴＥＡ ： トリエチルアミン
ＥｔＯＨ ： エタノール
ＬＡＨ ： 水素化リチウムアルミニウム
ＤＭＡ ： Ｎ，Ｎ－ジメチルアセトアミド
ＬＤＡ： リチウムジイソプロピルアミド
Ｂｏｃ： ｔｅｒｔ－ブトキシカルボニル
Ｚ： ベンジルオキシカルボニル The meanings of the abbreviations and symbols used in the following explanations are as follows.
DCM: dichloromethane THF: Tetrahydrofuran DMF: N, N-dimethylformamide TEA: Triethylamine EtOH: Ethanol LAH: Lithium hydride aluminum DMA: N, N-dimethylacetamide LDA: Lithium diisopropylamide Boc: tert-butoxycarbonyl Z: benzyloxycarbonyl
［本発明の化合物（Ｉ）の製法］
　式（Ｉ）で表される本発明の化合物は、例えばスキーム１によって製造することができる。
Figure JPOXMLDOC01-appb-C000006
 （式中、Ａ１、Ａ２、Ｌ、Ｒ１およびＲ２は前記（Ｉ）の記載と同義であり、ＰＧは保護基を表す。） [Method for producing compound (I) of the present invention]
The compound of the present invention represented by the formula (I) can be produced, for example, by Scheme 1.
Figure JPOXMLDOC01-appb-C000006
 (In the formula, A 1 , A 2 , L, R 1 and R 2 have the same meaning as described in (I) above, and PG represents a protecting group.)
　本発明の化合物（Ｉ）は、化合物（ＩＩ）を脱保護後、溶媒中、１，１’－カルボニルジイミダゾール（ＣＤＩ）や炭酸ジ（Ｎ－スクシンイミジル）（ＤＳＣ）などの縮合剤と反応させることによって得ることができる。目的物は、例えば、化合物（ＩＩ）を脱保護後、過剰量の縮合剤と反応させることで得ることができるが、好ましくは１～５モル当量のＣＤＩやＤＳＣと反応させることによって合成することができる。溶媒は反応に不活性なものであればいずれでもよく、特に限定されるものではないが、例えばＴＨＦ、好ましくはＤＭＦを用いることができる。反応は０℃から室温の範囲において、数分から数時間で実施することができるが、好ましくはＤＭＦ中で室温下、３０分間反応させることにより合成することができる。 The compound (I) of the present invention deprotects the compound (II) and then reacts with a condensing agent such as 1,1'-carbonyldiimidazole (CDI) or dicarbonate (N-succinimidyl) (DSC) in a solvent. Can be obtained by The desired product can be obtained, for example, by deprotecting compound (II) and then reacting it with an excess amount of a condensing agent, but preferably by reacting it with 1 to 5 molar equivalents of CDI or DSC. Can be done. The solvent may be any solvent as long as it is inert to the reaction, and is not particularly limited, but for example, THF, preferably DMF, can be used. The reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several hours, but is preferably synthesized by reacting in DMF at room temperature for 30 minutes.
　また、スキーム１の原料として用いられる化合物（ＩＩ）は例えばスキーム２に示す方法によって製造することができる。
Figure JPOXMLDOC01-appb-C000007
 　（式中、Ａ１、Ａ２、Ｌ、Ｒ1およびＲ2は前記（Ｉ）の記載と同義であり、ＰＧは保護基を表す。） Further, the compound (II) used as a raw material of Scheme 1 can be produced, for example, by the method shown in Scheme 2.
Figure JPOXMLDOC01-appb-C000007
 (In the formula, A 1 , A 2 , L, R 1 and R 2 have the same meaning as described in (I) above, and PG represents a protecting group.)
　化合物（ＩＩ）は、例えばイソチオシアネート（ＩＩＩ）とアミン（ＩＶ）を反応させて得られるチオウレア（Ｖ）を溶媒中、臭素もしくは臭素化試薬と反応させてチアゾール環を形成さることによっても製造することができる。まず、イソチオシアネート（ＩＩＩ）をエタノールなどの溶媒中、ナトリウムエトキシドなどの塩基存在下、もしくは非存在下、イソチオシアネート（ＩＩＩ）に対して、１～１．５モル当量のアミン（ＩＶ）と反応させることによってチオウレア（Ｖ）を得る。反応は０℃から室温の範囲において、数分～数日間で実施することができるが、好ましくは室温下、１日間反応させることにより合成することができる。 Compound (II) is also produced, for example, by reacting thiourea (V) obtained by reacting isothiocyanate (III) with amine (IV) in a solvent with a bromine or a brominated reagent to form a thiazole ring. be able to. First, isothiocyanate (III) is mixed with 1 to 1.5 molar equivalent amine (IV) with respect to isothiocyanate (III) in a solvent such as ethanol in the presence or absence of a base such as sodium ethoxide. Thiourea (V) is obtained by reacting. The reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several days, but is preferably synthesized by reacting at room temperature for one day.
　次いで、アセトニトリルなどの溶媒中、チオウレア（Ｖ）に対して、大過剰の酢酸および０．９～１モル当量の臭素、もしくはチオウレア（Ｖ）に対して、５～１０モル当量の炭酸水素ナトリウムおよび０．９～１モル当量のベンジルトリメチルアンモニウムトリブロミド等の臭素化試薬と反応させることによって、化合物（ＩＩ）を得ることができる。反応は０℃から室温の範囲において、数分～数日間で実施することができるが、好ましくは室温下、１日間反応させることにより合成することができる。
　スキーム２の原料として用いられるイソチオシアネート（ＩＩＩ）およびアミン（ＩＶ）は、市販品として入手するか、または公知の方法あるいは有機合成化学で通常用いられる方法によって製造することができる。 Then, in a solvent such as acetonitrile, a large excess of acetic acid with respect to thiourea (V) and 0.9 to 1 molar equivalent of bromine, or 5 to 10 molar equivalents of sodium hydrogencarbonate with respect to thiourea (V) and. Compound (II) can be obtained by reacting with a brominated reagent such as 0.9 to 1 molar equivalent of benzyltrimethylammonium tribromid. The reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several days, but is preferably synthesized by reacting at room temperature for one day.
The isothiocyanate (III) and amine (IV) used as raw materials for Scheme 2 can be obtained as commercial products, or can be produced by a known method or a method usually used in synthetic organic chemistry.
　また、スキーム１の原料として用いられる化合物（ＩＩ）は例えばスキーム３に示す方法によっても製造することができる。
Figure JPOXMLDOC01-appb-C000008
 　（式中、Ａ１、Ａ２、Ｌ、Ｒ1およびＲ2は前記（Ｉ）の記載と同義であり、ＰＧは保護基を表す。） Further, the compound (II) used as a raw material of Scheme 1 can also be produced, for example, by the method shown in Scheme 3.
Figure JPOXMLDOC01-appb-C000008
 (In the formula, A 1 , A 2 , L, R 1 and R 2 have the same meaning as described in (I) above, and PG represents a protecting group.)
　化合物（ＩＩ）は、例えばイソチオシアネート（VＩ）とアミン（ＩＶ）を反応させて得られるチオウレア（ＶＩＩ）を溶媒中、ウルマン（Ullman）型縮合によりチアゾール環を形成させ、その後、脱保護することによって製造することができる。すなわち、まず、エタノールなどの溶媒中、ナトリウムエトキシドなどの塩基存在下、もしくは非存在下、イソチオシアネート（VＩ）に対して、１～１．５モル当量のアミン（ＩＶ）と反応させることによってチオウレア（ＶＩＩ）を得る。反応は０℃から室温の範囲において、数分～数日間で実施することができるが、好ましくは室温下、１日間反応させることにより合成することができる。 Compound (II) is prepared by forming a thiazole ring by Ullman-type condensation in a solvent of thiourea (VII) obtained by reacting, for example, isothiocyanate (VI) with amine (IV), and then deprotecting the compound (II). Can be manufactured by. That is, first, by reacting isothiocyanate (VI) with 1 to 1.5 molar equivalents of amine (IV) in a solvent such as ethanol in the presence or absence of a base such as sodium ethoxide. Obtain thiourea (VII). The reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several days, but is preferably synthesized by reacting at room temperature for one day.
　次いで、アセトニトリルなどの溶媒中、チオウレア（ＶＩＩ）に対して、炭酸セシウムなどの塩基存在下、触媒として０．１～０．５モル当量のヨウ化銅（Ｉ）および０．１～０．５モル当量１，１０－フェナントロリンなどの配位子を添加して加熱することによって、化合物（ＩＩ）を得ることができる。反応は室温から還流温度の範囲において、数分～数日間で実施することができるが、好ましくは室温または還流温度で、１時間反応させることにより合成することができる。 Then, in a solvent such as acetonitrile, with respect to thiourea (VII), in the presence of a base such as cesium carbonate, 0.1 to 0.5 molar equivalents of copper (I) iodide and 0.1 to 0.5 as a catalyst Compound (II) can be obtained by adding and heating a ligand such as a molar equivalent of 1,10-phenanthroline. The reaction can be carried out in the range of room temperature to reflux temperature for several minutes to several days, but is preferably synthesized by reacting at room temperature or reflux temperature for 1 hour.
　スキーム３の原料として用いられるイソチオシアネート（VＩ）は、市販品として入手するか、または公知の方法あるいは有機合成化学で通常用いられる方法によって製造することができる。 The isothiocyanate (VI) used as a raw material of Scheme 3 can be obtained as a commercial product, or can be produced by a known method or a method usually used in synthetic organic chemistry.
　また、スキーム１の原料として用いられる化合物（ＩＩ）は例えばスキーム４に示す方法によっても製造することができる。
Figure JPOXMLDOC01-appb-C000009
 （式中、Ａ１、Ａ２、Ｌ、Ｒ１およびＲ２は前記（Ｉ）の記載と同義であり、Ｒはアルキル基を表し、ＰＧは保護基を表す。）
　化合物（ＩＩ）は、例えば化合物（ＶＩＩＩ）をＴＨＦ、アセトニトリル、ＤＭＡなどの溶媒中または無溶媒で、アミン（ＩＶ）と反応させることによって製造することができる。例えば、化合物（ＶＩＩＩ）に対して、３～１０モル当量のアミン（ＩＶ）と反応させることによって製造できる。反応は室温から１５０℃の範囲において、数分から数日間で実施することができるが、好ましくは１２０℃下、１日間反応させることにより、化合物（ＩＩ）を合成することができる。 Further, the compound (II) used as a raw material of Scheme 1 can also be produced, for example, by the method shown in Scheme 4.
Figure JPOXMLDOC01-appb-C000009
 (In the formula, A 1 , A 2 , L, R 1 and R 2 have the same meaning as described in (I) above, R represents an alkyl group and PG represents a protecting group.)
Compound (II) can be produced, for example, by reacting compound (VIII) with an amine (IV) in a solvent such as THF, acetonitrile or DMA or in the absence of a solvent. For example, it can be produced by reacting compound (VIII) with 3-10 molar equivalents of amine (IV). The reaction can be carried out in the range of room temperature to 150 ° C. for several minutes to several days, but the compound (II) can be synthesized by reacting at 120 ° C. for one day.
　なお、化合物（Ｉ’）の製造については、上記スキーム２～４において、アミンの立体異性体（ＩＶ’）を用いて、化合物（ＩＩ）の立体異性体（ＩＩ’）を合成し、スキーム１に従って反応を行うことにより、目的物を得ることができる。
Figure JPOXMLDOC01-appb-C000010
 （式中、Ａ１、Ａ２、Ｌ、Ｒ１、Ｒ２は前記（Ｉ）の記載と同義であり、ＰＧは保護基を表す。） Regarding the production of the compound (I'), in the above schemes 2 to 4, the stereoisomer (II') of the compound (II) is synthesized by using the stereoisomer (IV') of the amine, and the scheme 1 The desired product can be obtained by carrying out the reaction according to the above.
Figure JPOXMLDOC01-appb-C000010
 (In the formula, A 1 , A 2 , L, R 1 , and R 2 have the same meaning as described in (I) above, and PG represents a protecting group.)
　また、スキーム４の原料として用いられる化合物（ＶＩＩＩ）は例えばスキーム５に示す方法によって製造することができる。
Figure JPOXMLDOC01-appb-C000011
 （式中、Ａ１、Ａ２およびＬは前記（Ｉ）の記載と同義であり、Ｒはアルキル基を表し、Ｒ-Ｘはハロゲン化アルキルを表す。）
　最初に化合物（Ｘ）は、化合物（ＩＸ）を溶媒中、強塩基存在下、二酸化炭素と反応させることによって製造することができる。例えば、ＴＨＦなどの溶媒中、ＬＤＡなどの強塩基存在下、炭酸ガスを吹き込み反応させることによって得ることができる。反応は－８０℃から－７０℃の範囲において、数分から数時間で実施することができるが、好ましくはＴＨＦ中で－７８℃下、４５分間反応させることにより合成することができる。原料として用いられる化合物（ＩＸ）は、市販品として入手するか、または公知の方法あるいは有機合成化学で通常用いられる方法によって製造することができる。 Further, the compound (VIII) used as a raw material of Scheme 4 can be produced, for example, by the method shown in Scheme 5.
Figure JPOXMLDOC01-appb-C000011
 (In the formula, A 1 , A 2 and L are synonymous with the description in (I) above, R represents an alkyl group, and R-X represents an alkyl halide.)
First, compound (X) can be produced by reacting compound (IX) with carbon dioxide in a solvent in the presence of a strong base. For example, it can be obtained by blowing carbon dioxide gas into a solvent such as THF and in the presence of a strong base such as LDA. The reaction can be carried out in the range of −80 ° C. to −70 ° C. for several minutes to several hours, but is preferably synthesized by reacting in THF at −78 ° C. for 45 minutes. The compound (IX) used as a raw material can be obtained as a commercial product, or can be produced by a known method or a method usually used in synthetic organic chemistry.
　次に、化合物（Ｘ）のカルボキシル基をクルチウス転位によりイソシアネートに変換し、その後、酸で処理することによって化合物（ＸＩ）を製造することができる。あるいは、クルチウス転位により得られたイソシアネートを、ｔｅｒｔ－ブチルアルコールやベンジルアルコールと反応させることで、Ｂｏｃ基やＺ基で保護されたアミン体を得ることができ、これらを有機合成化学で通常用いられる方法によって脱保護することによっても、化合物（ＸＩ）を製造することができる。例えば、ジオキサンなどの溶媒中、ＴＥＡなどの塩基存在下、化合物（Ｘ）を１．１～１．３モル当量のジフェニルホスホリルアジドおよび８～１０モル当量のｔｅｒｔ－ブチルアルコールと加熱反応させることによってアミノ基がＢｏｃ保護された化合物（ＸＩ）を得ることができる。反応は１００℃から還流温度の範囲において、３時間～１日間で実施することができるが、好ましくはジオキサン中、１００℃で、４時間反応させることにより合成することができる。 Next, the carboxyl group of compound (X) can be converted to isocyanate by Curtius rearrangement, and then treated with acid to produce compound (XI). Alternatively, the isocyanate obtained by the Curtius rearrangement can be reacted with tert-butyl alcohol or benzyl alcohol to obtain an amine compound protected by a Boc group or a Z group, which are usually used in synthetic organic chemistry. Compound (XI) can also be produced by deprotection by the method. For example, by heating compound (X) with 1.1 to 1.3 molar equivalents of diphenylphosphoryl azide and 8 to 10 molar equivalents of tert-butyl alcohol in a solvent such as dioxane in the presence of a base such as TEA. A compound (XI) in which the amino group is Boc-protected can be obtained. The reaction can be carried out in the range of 100 ° C. to the reflux temperature for 3 hours to 1 day, but can be synthesized by reacting in dioxane at 100 ° C. for 4 hours.
　次いで、化合物（ＸＩＩ）は、化合物（ＸＩ）を溶媒中、エチルキサントゲン酸カリウムと加熱することによって製造できる。例えば、ＤＭＦなどの溶媒中、化合物（ＸＩ）に対して、２．５～３モル当量のエチルキサントゲン酸カリウムと加熱反応させることによって化合物（ＸＩＩ）を得ることができる。反応は９０℃から還流温度の範囲において、数分～数日間で実施することができるが、好ましくは１２０℃下、２日間反応させることにより合成することができる。 Next, compound (XII) can be produced by heating compound (XI) with potassium ethylxanthogenate in a solvent. For example, compound (XII) can be obtained by subjecting compound (XI) to a heat reaction with 2.5 to 3 molar equivalents of potassium ethylxanthogenate in a solvent such as DMF. The reaction can be carried out in the range of 90 ° C. to the reflux temperature for several minutes to several days, but is preferably synthesized by reacting at 120 ° C. for 2 days.
　次いで、化合物（ＸＩＩＩ）は、化合物（ＸＩＩ）を溶媒中、塩基存在下、ハロゲン化アルキルと反応させることによって製造できる。例えば、ＤＭＦなどの溶媒中、化合物（ＸＩＩ）に対して、炭酸カリウムなどの塩基存在下、３～４モル当量のヨウ化エチルなどのハロゲン化アルキルと反応させることによって化合物（ＸＩＩＩ）を得ることができる。反応は０℃から室温の範囲において、数分～数日間で実施することができるが、好ましくは室温下、２時間反応させることにより合成することができる。 Next, the compound (XIII) can be produced by reacting the compound (XII) with an alkyl halide in a solvent in the presence of a base. For example, compound (XIII) is obtained by reacting compound (XII) with an alkyl halide such as ethyl iodide in an amount of 3 to 4 molar equivalents in the presence of a base such as potassium carbonate in a solvent such as DMF. Can be done. The reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to several days, but is preferably synthesized by reacting at room temperature for 2 hours.
　最後に、化合物（ＶＩＩＩ）は、化合物（ＸＩＩＩ）を溶媒中、酸化することによって得ることができる。溶媒は反応に不活性なものであればいずれでもよく、特に限定されるものではないが、例えば、酢酸、水あるいはＤＣＭを用いることができる。本反応で用いられる酸化剤は、メタクロロ過安息香酸（ｍ－ＣＰＢＡ）や過酸化水素等の過酸化物やＫＭｎＯ４（過マンガン酸カリウム）などの通常の有機合成で用いられる酸化剤を用いることができ、例えば化合物（ＸＩＩＩ）に対して、０．８～２．５モル当量のｍ－ＣＰＢＡあるいは２～２．５モル当量のＫＭｎＯ４を用いることができる。反応は０℃から室温の範囲において、３０分間～２日間で実施することができるが、好ましくは室温条件下、３０分間反応させることにより合成することができる。 Finally, compound (VIII) can be obtained by oxidizing compound (XIII) in a solvent. The solvent may be any one as long as it is inert to the reaction, and is not particularly limited, and for example, acetic acid, water or DCM can be used. The oxidizing agent used in this reaction should be a peroxide such as meta-chloroperbenzoic acid (m-CPBA) or hydrogen peroxide, or an oxidizing agent used in ordinary organic synthesis such as KMnO 4 (potassium permanganate). For example, 0.8 to 2.5 mol equivalents of m-CPBA or 2 to 2.5 mol equivalents of KMnO 4 can be used with respect to compound (XIII). The reaction can be carried out in the range of 0 ° C. to room temperature for 30 minutes to 2 days, but is preferably synthesized by reacting for 30 minutes under room temperature conditions.
　スキーム５の原料として用いられる化合物（ＩＸ）は、市販品として入手するか、または公知の方法あるいは有機合成化学で通常用いられる方法によって製造することができる。 The compound (IX) used as a raw material for Scheme 5 can be obtained as a commercial product, or can be produced by a known method or a method usually used in synthetic organic chemistry.
　また、本発明の化合物のうち、Ｒ１が－ＣＨ２ＮＲ３Ｒ４を表す場合である化合物（Ｉ－１）は例えばスキーム６によって製造することができる。
Figure JPOXMLDOC01-appb-C000012
 　（式中、Ａ１、Ａ２、Ｌ、Ｒ３およびＲ４は前記（Ｉ）の記載と同義であり、Ｘはハロゲン原子、置換スルホニル基などの脱離基を表す。）
　本発明の化合物（Ｉ－１）は化合物（ＸＩＶ）に対して、ＴＨＦ、アセトニトリル、ＤＭＡなどの溶媒中または無溶媒で過剰量の１～２０モル当量のアミン（ＸＶ）と求核置換反応させることで化合物（Ｉ－１）得ることができる。反応は室温から還流温度の範囲において、数時間から数日で実施することができるが、好ましくはＴＨＦ、アセトニトリルまたはこれらの混合溶媒中、還流温度で１日間反応させることにより合成することができる。 Further, among the compounds of the present invention, the compound (I-1) in which R 1 represents −CH 2 NR 3 R 4 can be produced, for example, by Scheme 6.
Figure JPOXMLDOC01-appb-C000012
 (In the formula, A 1 , A 2 , L, R 3 and R 4 have the same meaning as described in (I) above, and X represents a leaving group such as a halogen atom or a substituted sulfonyl group.)
The compound (I-1) of the present invention causes a nucleophilic substitution reaction of compound (XIV) with an excess amount of 1 to 20 molar equivalents of amine (XV) in a solvent such as THF, acetonitrile or DMA or without a solvent. This makes it possible to obtain compound (I-1). The reaction can be carried out in the range of room temperature to reflux temperature for several hours to several days, but is preferably synthesized by reacting in THF, acetonitrile or a mixed solvent thereof at reflux temperature for 1 day.
　スキーム６の原料として用いられるアミン（ＸＶ）は、市販品として入手するか、または公知の方法あるいは有機合成化学で通常用いられる方法によって製造することができる。 The amine (XV) used as a raw material for Scheme 6 can be obtained as a commercial product, or can be produced by a known method or a method usually used in synthetic organic chemistry.
　前述の（１）～（１４）の化合物は、式（Ｉ）および式（Ｉ’）においてＡ１、Ａ２がそれらと結合する芳香環およびリンカーＬと一緒になって５員環または６員環を形成する化合物であるが、上記の製法のいずれかにより製造できる。 The above-mentioned compounds (1) to (14) are 5-membered rings or 6-membered compounds in the formulas (I) and (I') together with the aromatic ring and the linker L to which A 1 and A 2 are bonded. Although it is a compound that forms a ring, it can be produced by any of the above-mentioned production methods.
［本発明の化合物（Ｉ）の用途］
　本発明の式（Ｉ）および式（Ｉ’）で表される化合物またはその薬学的に許容される塩は、経口投与、非経口投与または局所的投与に適した従来の薬学製剤（医薬組成物）の形態に調製することができる。 [Use of compound (I) of the present invention]
The compounds represented by the formulas (I) and (I') of the present invention or pharmaceutically acceptable salts thereof are conventional pharmaceutical preparations (pharmaceutical compositions) suitable for oral administration, parenteral administration or topical administration. ) Can be prepared.
　経口投与のための製剤は、錠剤、顆粒、粉末、カプセルなどの固形剤、およびシロップなどの液体製剤を含む。これらの製剤は従来の方法によって調製することができる。固形剤は、ラクトース、コーンスターチなどのデンプン、微結晶性セルロースなどの結晶セルロース、ヒドロキシプロピルセルロース、カルシウムカルボキシメチルセルロース、タルク、ステアリン酸マグネシウムなどのような従来の薬学的担体を用いることによって調製することができる。カプセルは、このように調製した顆粒または粉末をカプセルに包むことによって調製することができる。シロップは、ショ糖、カルボキシメチルセルロースなどを含む水溶液中で、本発明の式（Ｉ）および式（Ｉ’）で表される化合物またはその薬学的に許容される塩を溶解または懸濁することによって調製することができる。 Formulations for oral administration include solid preparations such as tablets, granules, powders and capsules, and liquid preparations such as syrup. These formulations can be prepared by conventional methods. Solids can be prepared by using conventional pharmaceutical carriers such as lactose, starch such as cornstarch, crystalline cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, calcium carboxymethyl cellulose, talc, magnesium stearate and the like. can. Capsules can be prepared by encapsulating the granules or powders thus prepared. The syrup is prepared by dissolving or suspending the compound represented by the formulas (I) and (I') of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxymethyl cellulose and the like. Can be prepared.
　非経口投与のための製剤は、点滴注入などの注入物を含む。注入製剤もまた従来の方法によって調製することができ、等張化剤（例えば、マンニトール、塩化ナトリウム、グルコース、ソルビトール、グリセロール、キシリトール、フルクトース、マルトース、マンノース）、安定化剤（例えば、亜硫酸ナトリウム、アルブミン）、防腐剤（例えば、ベンジルアルコール、ｐ－オキシ安息香酸メチル）中に適宜組み入れることができる。 Formulations for parenteral administration include injections such as infusions. Injectable formulations can also be prepared by conventional methods, with isotonic agents (eg, mannitol, sodium chloride, glucose, sorbitol, glycerol, xylitol, fructose, maltose, mannose), stabilizers (eg, sodium sulfite, etc.). It can be appropriately incorporated into preservatives (eg, benzyl alcohol, methyl p-oxybenzoate).
　本発明の式（Ｉ）および式（Ｉ’）で表される化合物またはその薬学的に許容される塩の用量は、疾患の種類、重症度、患者の年齢、性別、および体重、投薬形態などに従って変化させることができるが、通常は成人において１日あたり１ｍｇ～１，０００ｍｇの範囲であり、それは経口経路または非経口経路によって、１回、または２回もしくは３回に分割して投与することができる。 The doses of the compounds represented by the formulas (I) and (I') of the present invention or pharmaceutically acceptable salts thereof include the type, severity, age, sex, body weight, dosage form, etc. of the disease. Usually in the range of 1 mg to 1,000 mg per day in adults, which may be administered in one, two or three divided doses by oral or parenteral route. Can be done.
　また、本発明の式（Ｉ）および式（Ｉ’）で表される化合物またはその薬学的に許容される塩は、ＤＹＲＫ阻害剤として、上記の疾患に関する病態イメージングの試薬や基礎実験用、研究用の試薬として用いることができる。 In addition, the compounds represented by the formulas (I) and the formula (I') of the present invention or pharmaceutically acceptable salts thereof can be used as DYRK inhibitors as reagents for pathological imagery related to the above-mentioned diseases, for basic experiments, and for research. Can be used as a reagent for.
以下に実施例および試験例などを挙げて本発明をさらに具体的に説明するが、これらの実施例により本発明が限定されるものではない。
　化合物の同定は水素核磁気共鳴スペクトル（1H-NMR）及びマススペクトル（ＭＳ）により行った。1H-NMRは、特に指示のないかぎりは400MHzで測定されたものであり、また化合物及び測定条件によっては交換性水素が明瞭に観測されない場合がある。なお、br.は幅広いシグナル（ブロード）を意味する。ＨＰＬＣ分取クロマトグラフィーは、市販のＯＤＳカラムを用い、特に記載のない限りは水／メタノール、あるいは水／アセトニトリル（ギ酸を含む）を溶出液としてグラジェントモードにて分取した。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples.
Compounds were identified by hydrogen nuclear magnetic resonance spectra ( 1 H-NMR) and mass spectra (MS). 1 H-NMR was measured at 400 MHz unless otherwise specified, and commutative hydrogen may not be clearly observed depending on the compound and measurement conditions. In addition, br. means a wide range of signals (broad). For HPLC preparative chromatography, a commercially available ODS column was used, and unless otherwise specified, water / methanol or water / acetonitrile (including formic acid) was used as an eluent and fractionated in a gradient mode.
参考例１
７－（エチルスルホニル）－［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾールの製造
Figure JPOXMLDOC01-appb-C000013
 （第１工程）
　ジイソプロピルアミン（１．３ｍＬ，９．２ｍｍｏｌ）のＴＨＦ溶液（４０ｍＬ）に、－８０℃で、ｎ－ブチルリチウム（１．６Ｍ ヘキサン溶液，５．７ｍＬ，９．１ｍｍｏｌ）を滴下し、２０分間撹拌した。この溶液に、４－ブロモ－１，２－（メチレンジオキシ）ベンゼン（１．０ｍＬ，８．４ｍｍｏｌ）のＴＨＦ溶液（１０ｍＬ）を滴下し、４０分間撹拌した。この溶液に炭酸ガスを吹き込みながら、４５分間撹拌した後、さらに室温で１９時間撹拌した。反応溶液に２Ｍ塩酸を加えて中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去後、析出した固体をろ取し、ヘキサンで洗浄後、乾燥させて４－ブロモ－３－カルボキシ－１，２－メチレンジオキシベンゼンを得た（収量１．１ｇ）。
1H NMR (DMSO-d6) δ (ppm) 13.66 (br. s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.13 (s, 2H) Reference example 1
Production of 7- (ethylsulfonyl)-[1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole
Figure JPOXMLDOC01-appb-C000013
 (First step)
To a THF solution (40 mL) of diisopropylamine (1.3 mL, 9.2 mmol), n-butyllithium (1.6 M hexane solution, 5.7 mL, 9.1 mmol) was added dropwise at -80 ° C, and the mixture was stirred for 20 minutes. did. A THF solution (10 mL) of 4-bromo-1,2- (methylenedioxy) benzene (1.0 mL, 8.4 mmol) was added dropwise to this solution, and the mixture was stirred for 40 minutes. The solution was stirred for 45 minutes while blowing carbon dioxide gas, and then further stirred at room temperature for 19 hours. 2M Hydrochloric acid was added to the reaction solution for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the precipitated solid was collected by filtration, washed with hexane, and dried to obtain 4-bromo-3-carboxy-1,2-methylenedioxybenzene (yield 1.1 g).
1 H NMR (DMSO-d 6 ) δ (ppm) 13.66 (br. S, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.13 (s, 2H)
（第２工程）
　４－ブロモ－３－カルボキシ－１，２－メチレンジオキシベンゼン（１．０ｇ，４．１ｍｍｏｌ）のジオキサン溶液（１５ｍＬ）に、室温でＴＥＡ（０．６３ｍＬ，４．５ｍｍｏｌ）、ｔｅｒｔ－ブタノール（３．２ｍＬ，３４ｍｍｏｌ）およびジフェニルホスホリルアジド（０．９７ｍＬ，４．５ｍｍｏｌ）を加え、３時間加熱還流した。反応溶液を水で希釈し、酢酸エチルで抽出後、有機層を飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去後、乾燥させた。この中間体の酢酸エチル溶液（６．０ｍＬ）に、氷冷で４Ｍ塩化水素－酢酸エチル溶液（１０ｍＬ，４０ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応溶液に２Ｍ水酸化ナトリウム水溶液を加えて中和し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去後、残渣をカラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）で精製し、３－アミノ－４－ブロモ－１，２－メチレンジオキシベンゼンを得た（収量０．８０ｇ）。
1H NMR (DMSO-d6) δ (ppm) 6.89 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 5.98 (s, 2H), 5.05 (br. s, 2H) (Second step)
TEA (0.63 mL, 4.5 mmol), tert-butanol (0.63 mL, 4.5 mmol) in a dioxane solution (15 mL) of 4-bromo-3-carboxy-1,2-methylenedioxybenzene (1.0 g, 4.1 mmol) at room temperature. 3.2 mL, 34 mmol) and diphenylphosphoryl azide (0.97 mL, 4.5 mmol) were added, and the mixture was heated under reflux for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and then dried. A 4M hydrogen chloride-ethyl acetate solution (10 mL, 40 mmol) was added to the ethyl acetate solution (6.0 mL) of this intermediate by ice-cooling, and the mixture was stirred at room temperature for 16 hours. A 2M aqueous sodium hydroxide solution was added to the reaction solution for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain 3-amino-4-bromo-1,2-methylenedioxybenzene (yield 0.80 g).
1 1 H NMR (DMSO-d 6 ) δ (ppm) 6.89 (d, J = 8.4 Hz, 1H), 6.22 (d, J = 8.4 Hz, 1H), 5.98 (s, 2H), 5.05 (br. S, 2H)
（第３工程）
　３－アミノ－４－ブロモ－１，２－メチレンジオキシベンゼン（０．７９ｇ，３．１ｍｍｏｌ）のＤＭＦ溶液（１５ｍＬ）に、室温でキサントゲン酸カリウム（１．２ｇ，７．３ｍｍｏｌ）を加え、１２０℃で５日間撹拌した。この反応溶液に、氷冷で炭酸カリウム（２．２ｇ，ｍｍｏｌ）およびヨウ化エチル（０．７６ｍＬ，９．４ｍｍｏｌ）を加え、室温で２時間撹拌した。反応溶液を水で希釈し、酢酸エチルで抽出後、有機層を飽和炭酸水素ナトリウム水溶液、水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去後、残渣をカラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）で精製し、７－（エチルチオ）－［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾールを得た（収量０．２６ｇ）。
1H NMR (DMSO-d6) δ (ppm) 7.46 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.16 (s, 2H), 3.28 - 3.41 (m, 2H), 1.41 (t, J = 7.3 Hz, 3H)   (Third step)
Potassium xanthate (1.2 g, 7.3 mmol) was added to a DMF solution (15 mL) of 3-amino-4-bromo-1,2-methylenedioxybenzene (0.79 g, 3.1 mmol) at room temperature. The mixture was stirred at 120 ° C. for 5 days. Potassium carbonate (2.2 g, mmol) and ethyl iodide (0.76 mL, 9.4 mmol) were added to this reaction solution by ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, hexane / ethyl acetate), and 7- (ethylthio)-[1,3] dioxolo [4', 5': 5,6] benzo [1]. , 2-d] Thiazole was obtained (yield 0.26 g).
1 H NMR (DMSO-d 6 ) δ (ppm) 7.46 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.16 (s, 2H), 3.28 --3.41 (m, 2H), 1.41 (t, J = 7.3 Hz, 3H)
（第４工程）
　７－（エチルチオ）－［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール（０．１４ｇ，０．５９ｍｍｏｌ）のＤＣＭ溶液（２．０ｍＬ）に、氷冷でｍ－クロロ過安息香酸（０．３６ｇ，０．４８ｍｍｏｌ）を加え、室温で１日間撹拌した。反応溶液を水で希釈し、酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去後、残渣をカラムクロマトグラフィー（シリカゲル、クロロホルム）で精製し、表題化合物を得た（収量０．１１ｇ）。
1H NMR (DMSO-d6) δ (ppm) 7.81 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 6.30 (s, 2H), 3.70 (q, J = 7.3 Hz, 2H), 1.27 (t, J = 7.3 Hz, 3H) (4th step)
In a DCM solution (2.0 mL) of 7- (ethylthio)-[1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole (0.14 g, 0.59 mmol). , M-Chloroperoxybenzoic acid (0.36 g, 0.48 mmol) was added by ice-cooling, and the mixture was stirred at room temperature for 1 day. The reaction solution was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, chloroform) to give the title compound (yield 0.11 g).
1 H NMR (DMSO-d 6 ) δ (ppm) 7.81 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 6.30 (s, 2H), 3.70 (q, J = 7.3 Hz, 2H), 1.27 (t, J = 7.3 Hz, 3H)
参考例２
２－（エチルスルホニル）チアゾロ［４，５－ｆ］キノキサリンの製造
Figure JPOXMLDOC01-appb-C000014
 （第１工程）
　４－ブロモ－３－ニトロベンゼン－１,２－ジアミン（０．５ｇ，２．２ｍｍｏｌ）のＥｔＯＨ溶液（７．５ｍＬ）に、室温で３９％グリオキサール水溶液（０．７５ｍＬ，６．６ｍｍｏｌ）を加え、１時間加熱還流した。溶媒を減圧留去後、水で希釈し、酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥させた。溶媒を減圧留去後、残渣をカラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）で精製し、６－ブロモ－５－ニトロキノキサリンを得た（収量０．４２ｇ）。
1H NMR (DMSO-d6) δ (ppm) 9.18 (d, J = 1.8 Hz, 1H), 9.11 (d, J = 1.8 Hz, 1H), 8.25 - 8.35 (m, 2H) Reference example 2
Production of 2- (Ethylsulfonyl) thiazolo [4,5-f] quinoxaline
Figure JPOXMLDOC01-appb-C000014
 (First step)
A 39% aqueous glyoxal solution (0.75 mL, 6.6 mmol) was added to an EtOH solution (7.5 mL) of 4-bromo-3-nitrobenzene-1,2-diamine (0.5 g, 2.2 mmol) at room temperature. The mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, hexane / ethyl acetate) to obtain 6-bromo-5-nitroquinoxaline (yield 0.42 g).
1 H NMR (DMSO-d 6 ) δ (ppm) 9.18 (d, J = 1.8 Hz, 1H), 9.11 (d, J = 1.8 Hz, 1H), 8.25 --8.35 (m, 2H)
（第２工程）
　６－ブロモ－５－ニトロキノキサリン（０．４２ｇ，１．７ｍｍｏｌ）の８６％ＥｔＯＨ水溶液（３．５ｍＬ）に、室温で鉄（０．４８ｇ，８．５ｍｍｏ１）および塩化アンモニウム（０．０１８ｇ，０．３４ｍｍｏ１）を加え、１日間加熱還流した。反応溶液を室温まで放冷後、セライトを用いて不溶物をろ過した。ろ液を減圧濃縮し、残渣をカラムクロマトグラフィー（シリカゲル、クロロホルム）で精製し、５－アミノ－６－ブロモキノキサリンを得た（収量０．２８ｇ）。
1H NMR (DMSO-d6) δ (ppm) 8.94 (d, J = 1.8 Hz, 1H), 8.81 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 9.0 Hz, 1H), 6.21 (s, 1H) (Second step)
Iron (0.48 g, 8.5 mmo1) and ammonium chloride (0.018 g, 0) in an 86% EtOH aqueous solution (3.5 mL) of 6-bromo-5-nitroquinoxaline (0.42 g, 1.7 mmol) at room temperature. .34 mmo1) was added, and the mixture was heated under reflux for 1 day. After allowing the reaction solution to cool to room temperature, the insoluble material was filtered using Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform) to obtain 5-amino-6-bromoquinoxaline (yield 0.28 g).
1 H NMR (DMSO-d 6 ) δ (ppm) 8.94 (d, J = 1.8 Hz, 1H), 8.81 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 9.0 Hz, 1H), 6.21 (s, 1H)
（第３工程）
　５－アミノ－６－ブロモキノキサリンを用い、参考例１の第３工程記載の方法と同様にして得られた２－（エチルチオ）チアゾロ［４，５－ｆ］キノキサリンを、参考例１の第４工程記載の方法と同様に処理して、表題化合物を得た（収量０．０４１ｇ）。
1H NMR (CDCl3) δ (ppm) 9.12 (d, J = 1.9 Hz, 1H), 9.06 (d, J = 1.9 Hz, 1H), 8.26 - 8.36 (m, 2H), 3.74 (q, J = 7.4 Hz, 2H), 1.47 (t, J = 7.4 Hz, 3H) (Third step)
Using 5-amino-6-bromoquinoxaline, 2- (ethylthio) thiazolo [4,5-f] quinoxaline obtained in the same manner as in the method described in the third step of Reference Example 1 was used as the fourth of Reference Example 1. Treatment was carried out in the same manner as in the method described in the process to obtain the title compound (yield 0.041 g).
1 H NMR (CDCl 3 ) δ (ppm) 9.12 (d, J = 1.9 Hz, 1H), 9.06 (d, J = 1.9 Hz, 1H), 8.26 --8.36 (m, 2H), 3.74 (q, J = 7.4 Hz, 2H), 1.47 (t, J = 7.4 Hz, 3H)
参考例３
４－イソチオシアネート－２，３－ジヒドロベンゾフランの製造
Figure JPOXMLDOC01-appb-C000015
 ２，３－ジヒドロベンゾフラン－４－アミン（１．０ｇ，　７．４１ｍｍｏｌ）の水溶液（１０ｍＬ）にチオホスゲン（１．４１ｍＬ，　１８．５２ｍｍｏｌ）を０℃で加えて、混合物を室温で４時間撹拌した。反応完結後、反応混合物を水で希釈し、酢酸エチルで抽出した。有機層を水および飽和食塩溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を減圧下濃縮し、残渣をカラムクロマトグラフィー（シリカゲル、石油エーテル）で精製して、４－イソチオシアネート－２，３－ジヒドロベンゾフラン（０．９ｇ）を得た。
1H NMR (400MHz, CDCl3) δ = 7.07 (t, J = 8.0 Hz, 1H), 6.70 (dd, J = 1.1, 7.9 Hz, 2H), 4.62 (t, J = 8.8 Hz, 2H), 3.30 (t, J = 8.6 Hz, 2H). GC-MS: 177.1 (M+). Reference example 3
Production of 4-isothiocyanate-2,3-dihydrobenzofuran
Figure JPOXMLDOC01-appb-C000015
 Thiophosgene (1.41 mL, 18.52 mmol) was added to an aqueous solution (10 mL) of 2,3-dihydrobenzofuran-4-amine (1.0 g, 7.41 mmol) at 0 ° C. and the mixture was stirred at room temperature for 4 hours. .. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated salt solution and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, petroleum ether) to obtain 4-isothiocyanate-2,3-dihydrobenzofuran (0.9 g).
1H NMR (400MHz, CDCl3) δ = 7.07 (t, J = 8.0 Hz, 1H), 6.70 (dd, J = 1.1, 7.9 Hz, 2H), 4.62 (t, J = 8.8 Hz, 2H), 3.30 (t) , J = 8.6 Hz, 2H). GC-MS: 177.1 (M + ).
実施例１
５－フェニル－１－（チアゾロ［４，５－ｆ］キノキサリン－２－イル）イミダゾリジン－２－オンの製造
Figure JPOXMLDOC01-appb-C000016
 （第１工程）
２－アミノ－１－フェニルエタノール（４ｍＬ，２９ｍｍｏｌ）のＴＨＦ溶液（０．１５Ｌ）に二炭酸ジ－ｔｅｒｔ－ブチル（７．５ｍＬ，３２ｍｍｏｌ）を加え、室温で２時間攪拌した。反応液を減圧濃縮して得られた固体をヘキサンと酢酸エチルの混合溶媒に懸濁させてろ過し、ヘキサンで洗浄後乾燥させて、ｔｅｒｔ－ブチル（２－ヒドロキシ－２－フェニルエチル）カーバメートを得た（収量５．８ｇ）。
1H NMR (CDCl3) δ (ppm) 7.24 - 7.40 (m, 5H), 4.95 (s, 1H), 4.76 - 4.89 (m, 1H), 3.39 - 3.56 (m, 1H), 3.19 - 3.31 (m, 1H), 3.12 (s, 1H), 1.45 (s, 9H) Example 1
Production of 5-Phenyl-1- (thiazolo [4,5-f] quinoxaline-2-yl) imidazolidine-2-one
Figure JPOXMLDOC01-appb-C000016
 (First step)
Di-tert-butyl dicarbonate (7.5 mL, 32 mmol) was added to a THF solution (0.15 L) of 2-amino-1-phenylethanol (4 mL, 29 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained solid was suspended in a mixed solvent of hexane and ethyl acetate, filtered, washed with hexane and dried to obtain tert-butyl (2-hydroxy-2-phenylethyl) carbamate. Obtained (yield 5.8 g).
1 1 H NMR (CDCl 3 ) δ (ppm) 7.24 --7.74 (m, 5H), 4.95 (s, 1H), 4.76 --4.89 (m, 1H), 3.39 --3.56 (m, 1H), 3.19 --3.31 (m) , 1H), 3.12 (s, 1H), 1.45 (s, 9H)
（第２工程）
ｔｅｒｔ－ブチル（２－ヒドロキシ－２－フェニルエチル）カーバメート（４．９ｇ，２１ｍｍｏｌ）のＴＨＦ溶液（８２ｍＬ）にフタルイミド（３．３ｇ，２３ｍｍｏｌ）、トリフェニルホスフィン（６．７ｇ，２６ｍｍｏｌ）を加え、次いでジエチルアゾジカルボキシレートの２．２Ｍトルエン溶液（１２ｍＬ，２６ｍｍｏｌ）をゆっくり滴下した。反応液を室温で一晩攪拌した後に減圧濃縮し、残渣をカラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）で精製した。この中間体をＥｔＯＨ（０．２０Ｌ）に溶解した後にヒドラジン一水和物（５ｍＬ，０．１ｍｏｌ）を加え、５０℃で一晩攪拌した。反応液をセライトろ過した後にろ液を濃縮し、残渣を酢酸エチルに溶解した。これを水、１Ｍ水酸化ナトリウム水溶液、飽和食塩水で順に洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去して、ｔｅｒｔ－ブチル（２－アミノ－２－フェニルエチル）カーバメートを得た（収量２ｇ）。 (Second step)
Add phthalimide (3.3 g, 23 mmol) and triphenylphosphine (6.7 g, 26 mmol) to a THF solution (82 mL) of tert-butyl (2-hydroxy-2-phenylethyl) carbamate (4.9 g, 21 mmol). Then a 2.2 M toluene solution of diethylazodicarboxylate (12 mL, 26 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane / ethyl acetate). After dissolving this intermediate in EtOH (0.20 L), hydrazine monohydrate (5 mL, 0.1 mol) was added, and the mixture was stirred at 50 ° C. overnight. The reaction mixture was filtered through cerite, the filtrate was concentrated, and the residue was dissolved in ethyl acetate. This was washed successively with water, 1M aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain tert-butyl (2-amino-2-phenylethyl) carbamate (yield 2 g).
（第３工程）
ｔｅｒｔ－ブチル（２－アミノ－２－フェニルエチル）カーバメート（０．６８ｇ，２．９ｍｏｌ）と参考例２で得られた２－（エチルスルホニル）チアゾロ［４，５－ｆ］キノキサリン（０．２ｇ，０．７２ｍｍｏｌ）の混合物を１２０℃で４時間攪拌した。反応液をクロロホルムで希釈し、カラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）で精製してｔｅｒｔ－ブチル［２－フェニル－２－（チアゾロ［４，５－ｆ］キノキサリン－２－イルアミノ）エチル］カーバメートを得た（収量０．１９ｇ）
1H NMR (DMSO-d6) δ (ppm) 8.82 - 8.93 (m, 3H), 8.17 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.39 - 7.49 (m, 2H), 7.29 - 7.42 (m, 2H), 7.21 - 7.33 (m, 1H), 7.02 - 7.09 (m, 1H), 5.17 (s, 1H), 3.34 - 3.42 (m, 2H), 1.33 (s, 9H) (Third step)
tert-butyl (2-amino-2-phenylethyl) carbamate (0.68 g, 2.9 mol) and 2- (ethylsulfonyl) thiazolo [4,5-f] quinoxaline (0.2 g) obtained in Reference Example 2. , 0.72 mmol) was stirred at 120 ° C. for 4 hours. The reaction mixture is diluted with chloroform, purified by column chromatography (silica gel, hexane / ethyl acetate), and purified by tert-butyl [2-phenyl-2- (thiazolo [4,5-f] quinoxaline-2-ylamino) ethyl]. Carbamate was obtained (yield 0.19 g)
1 H NMR (DMSO-d 6 ) δ (ppm) 8.82 --8.93 (m, 3H), 8.17 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.39 --7.49 ( m, 2H), 7.29 --7.42 (m, 2H), 7.21 --7.33 (m, 1H), 7.02 --7.09 (m, 1H), 5.17 (s, 1H), 3.34 --3.42 (m, 2H), 1.33 ( s, 9H)
（第４工程）
ｔｅｒｔ－ブチル［２－フェニル－２－（チアゾロ［４，５－ｆ］キノキサリン－２－イルアミノ）エチル］カーバメート（０．１９ｇ，０．４６ｍｍｏｌ）のＴＨＦ溶液（５ｍＬ）に４Ｍ塩化水素－ジオキサン溶液（５ｍＬ）を加え、室温で一晩攪拌した。反応液に水酸化ナトリウム水溶液を加えてアルカリ性とし、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去して１－フェニル－Ｎ１－（チアゾロ［４，５－ｆ］キノキサリン－２－イル）エタン－１，２－ジアミンを得た（収量４１ｍｇ）。
1H NMR (DMSO-d6) δ (ppm) 8.84 - 8.94 (m, 2H), 8.18 (d, J = 8.8 Hz, 1H), 7.66 - 7.74 (m, 1H), 7.21 - 7.51 (m, 5H), 5.09 (s, 1H), 3.03 (d, J = 6.6 Hz, 2H) (4th step)
4M hydrogen chloride-dioxane solution in THF solution (5 mL) of tert-butyl [2-phenyl-2- (thiazolo [4,5-f] quinoxaline-2-ylamino) ethyl] carbamate (0.19 g, 0.46 mmol). (5 mL) was added and stirred overnight at room temperature. An aqueous sodium hydroxide solution was added to the reaction solution to make it alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1-phenyl-N1- (thiazolo [4,5-f] quinoxaline-2-yl) ethane-1,2-diamine (yield 41 mg).
1 H NMR (DMSO-d 6 ) δ (ppm) 8.84 --8.94 (m, 2H), 8.18 (d, J = 8.8 Hz, 1H), 7.66 --7.74 (m, 1H), 7.21 --7.51 (m, 5H) ), 5.09 (s, 1H), 3.03 (d, J = 6.6 Hz, 2H)
（第５工程）
１－フェニル－Ｎ１－（チアゾロ［４，５－ｆ］キノキサリン－２－イル）エタン－１，２－ジアミン（４１ｍｇ，０．１３ｍｍｏｌ）のＤＭＦ溶液（２．０ｍＬ）に炭酸Ｎ，Ｎ’－ジスクシンイミジル（１００ｍｇ，０．３９ｍｍｏｌ）を加えた。室温で３０分間攪拌後、反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去し、残渣をカラムクロマトグラフィー（アミンシリカゲル、ヘキサン／酢酸エチル）で精製して表題化合物を得た（収量２２ｍｇ）。
1H NMR (DMSO-d6) δ (ppm) 8.89 - 8.97 (m, 2H), 8.38 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.32 - 7.43 (m, 4H), 7.22 - 7.32 (m, 1H), 5.93 (dd, J = 9.1, 2.3 Hz, 1H), 4.13 (t, J = 9.3 Hz, 1H), 3.27 - 3.32 (m, 1H); LCMS (m/z): 348.0 [M+H]+ (Fifth step)
1-Phenyl-N1- (thiazolo [4,5-f] quinoxaline-2-yl) ethane-1,2-diamine (41 mg, 0.13 mmol) in a DMF solution (2.0 mL) containing N, N'-carbonate. Discusin imidazole (100 mg, 0.39 mmol) was added. After stirring at room temperature for 30 minutes, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (amine silica gel, hexane / ethyl acetate) to give the title compound (yield 22 mg).
1 H NMR (DMSO-d 6 ) δ (ppm) 8.89 --8.97 (m, 2H), 8.38 (d, J = 8.8 Hz, 1H), 8.07 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.32 --7.43 (m, 4H), 7.22 --7.32 (m, 1H), 5.93 (dd, J = 9.1, 2.3 Hz, 1H), 4.13 (t, J = 9.3 Hz, 1H), 3.27 --3.32 (m, 1H); LCMS (m / z): 348.0 [M + H] +
実施例２
１－（［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール－７－イル）－５－フェニルイミダゾリジン－２－オンの製造
Figure JPOXMLDOC01-appb-C000017
 （第１工程）
参考例１で得られた７－（エチルスルホニル）－［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール（０．３ｇ，１．１ｍｍｏｌ）と、実施例１の第２工程で得られたｔｅｒｔ－ブチル（２－アミノ－２－フェニルエチル）カーバメート（１ｇ，４．４ｍｍｏｌ）を用い、実施例１の第３工程記載の方法と同様にして、粗精製のｔｅｒｔ－ブチル（２－［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール－７－イルアミノ）－２－フェニルエチル）カーバメートを得た（収量０．２５ｇ）。 Example 2
Production of 1-([1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-yl) -5-phenylimidazolidine-2-one
Figure JPOXMLDOC01-appb-C000017
 (First step)
With 7- (ethylsulfonyl)-[1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole (0.3 g, 1.1 mmol) obtained in Reference Example 1. Using tert-butyl (2-amino-2-phenylethyl) carbamate (1 g, 4.4 mmol) obtained in the second step of Example 1, the method described in the third step of Example 1 was carried out in the same manner. , Crude purified tert-butyl (2- [1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-ylamino) -2-phenylethyl) carbamate (Yield 0.25 g).
（第２工程）
ｔｅｒｔ－ブチル（２－［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール－７－イルアミノ）－２－フェニルエチル）カーバメート（０．２５ｇ，０．６１ｍｍｏｌ）を用い、実施例１の第４工程記載の方法と同様にして、Ｎ１－｛［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール－７－イル｝－１－フェニルエタン－１，２－ジアミンを得た（収量０．１２ｇ）。
1H NMR (DMSO-d6) δ (ppm) 8.60 (s, 1H), 7.27 - 7.42 (m, 4H), 7.19 - 7.30 (m, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 5.97 (dd, J = 8.5, 1.1 Hz, 2H), 4.81 (t, J = 6.4 Hz, 1H), 2.85 (d, J = 6.5 Hz, 2H), 1.52 (s, 2H) (Second step)
tert-butyl (2- [1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-ylamino) -2-phenylethyl) carbamate (0.25 g, 0) .61 mmol) and N1- {[1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole in the same manner as in the method described in the fourth step of Example 1. -7-Il} -1-phenylethane-1,2-diamine was obtained (yield 0.12 g).
1 H NMR (DMSO-d 6 ) δ (ppm) 8.60 (s, 1H), 7.27 --7.42 (m, 4H), 7.19 --7.30 (m, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 5.97 (dd, J = 8.5, 1.1 Hz, 2H), 4.81 (t, J = 6.4 Hz, 1H), 2.85 (d, J = 6.5 Hz, 2H), 1.52 (s, 2H)
（第３工程）
Ｎ１－｛［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール－７－イル｝－１－フェニルエタン－１，２－ジアミン（０．１２ｇ，０．３８ｍｍｏｌ）を用い、実施例１の第５工程記載の方法と同様にして表題化合物を得た（収量４３ｍｇ）。
1H NMR (DMSO-d6) δ (ppm) 7.99 (s, 1H), 7.23 - 7.41 (m, 6H), 6.88 (d, J = 8.3 Hz, 1H), 6.01 (dd, J = 12.2, 1.1 Hz, 2H), 5.73 (dd, J = 9.3, 2.7 Hz, 1H), 4.00 - 4.10 (m, 1H), 3.19 - 3.28 (m, 1H); LCMS (m/z): 339.9 [M+H]+ (Third step)
N1-{[1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-yl} -1-phenylethane-1,2-diamine (0.12 g, Using 0.38 mmol), the title compound was obtained in the same manner as in the method described in the fifth step of Example 1 (yield 43 mg).
1 H NMR (DMSO-d 6 ) δ (ppm) 7.99 (s, 1H), 7.23 --7.41 (m, 6H), 6.88 (d, J = 8.3 Hz, 1H), 6.01 (dd, J = 12.2, 1.1 Hz, 2H), 5.73 (dd, J = 9.3, 2.7 Hz, 1H), 4.00 --4.10 (m, 1H), 3.19 --3.28 (m, 1H); LCMS (m / z): 339.9 [M + H] + +
実施例３
１－（［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール－７－イル）－５－（メトキシメチル）イミダゾリジン－２－オンの製造
Figure JPOXMLDOC01-appb-C000018
 （第１工程）
グリシジルメチルエーテル（５ｇ，５７ｍｍｏｌ）を２８％アンモニア水溶液に溶解し、混合液を室温で４０時間攪拌した。溶媒を減圧留去し、残渣をＴＨＦ（４５ｍＬ）溶解した。この溶液にＴＥＡ（６．３ｍＬ，４５ｍｍｏｌ）と二炭酸ジ－ｔｅｒｔ－ブチル（９．８ｇ，４５ｍｍｏｌ）を加え、混合物を室温で２時間攪拌した。溶媒を減圧留去後、残渣を酢酸エチルで希釈し、水－飽和食塩水１：１の混合液で洗浄し、次いで溶媒を留去して粗精製のｔｅｒｔ－ブチル（２－ヒドロキシ－３－メトキシプロピル）カーバメートを得た（収量９ｇ）。 Example 3
Production of 1-([1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-yl) -5- (methoxymethyl) imidazolidine-2-one
Figure JPOXMLDOC01-appb-C000018
 (First step)
Glycidylmethyl ether (5 g, 57 mmol) was dissolved in a 28% aqueous ammonia solution, and the mixed solution was stirred at room temperature for 40 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in THF (45 mL). TEA (6.3 mL, 45 mmol) and di-tert-butyl dicarbonate (9.8 g, 45 mmol) were added to this solution, and the mixture was stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the residue is diluted with ethyl acetate, washed with a water-saturated saline 1: 1 mixture, and then the solvent is distilled off to make crude tert-butyl (2-hydroxy-3-3). A methoxypropyl) solvent was obtained (yield 9 g).
（第２工程）
ｔｅｒｔ－ブチル（２－ヒドロキシ－３－メトキシプロピル）カーバメート（９ｇ，４４ｍｍｏｌを用い、実施例１の第２工程の方法と同様にして、ｔｅｒｔ－ブチル（２－アミノ－３－メトキシプロピル）カーバメートを得た（収量７．６ｇ）。
1H NMR (CDCl3) δ (ppm) 4.92 - 5.02 (m, 1H), 3.37 (dd, J = 9.4, 4.3 Hz, 1H), 3.36 (s, 3H), 3.19 - 3.31 (m, 3H), 2.97 - 3.11 (m, 3H), 1.45 (s, 9H)  (Second step)
Using tert-butyl (2-hydroxy-3-methoxypropyl) carbamate (9 g, 44 mmol), tert-butyl (2-amino-3-methoxypropyl) carbamate was prepared in the same manner as in the second step method of Example 1. Obtained (yield 7.6 g).
1 1 H NMR (CDCl 3 ) δ (ppm) 4.92 --5.02 (m, 1H), 3.37 (dd, J = 9.4, 4.3 Hz, 1H), 3.36 (s, 3H), 3.19 --3.31 (m, 3H), 2.97 --3.11 (m, 3H), 1.45 (s, 9H)
（第３工程）
参考例１で得られた７－（エチルスルホニル）－［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール（０．１ｇ，０．３７ｍｍｏｌ）およびｔｅｒｔ－ブチル（２－アミノ－３－メトキシプロピル）カーバメート（０．３ｇ，１．５ｍｍｏｌ）を用い、実施例１の第３工程の方法と、続く第４工程の方法と同様にして、Ｎ２－（［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール－７－イル）－３－メトキシプロパン－１，２－ジアミンを得た（収量７５ｍｇ）。
1H NMR (CDCl3) δ (ppm) 7.01 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.04 (s, 2H), 5.82 (s, 1H), 4.04 (s, 1H), 3.55 - 3.68 (m, 2H), 3.38 (s, 3H), 3.05 (dd, J = 13.0, 5.4 Hz, 1H), 2.97 (dd, J = 13.0, 5.7 Hz, 1H) (Third step)
7- (Ethylsulfonyl)-[1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole (0.1 g, 0.37 mmol) obtained in Reference Example 1 and Using tert-butyl (2-amino-3-methoxypropyl) carbamate (0.3 g, 1.5 mmol), N2- in the same manner as in the method of the third step of Example 1 and the method of the subsequent fourth step. ([1,3] Dioxolo [4', 5': 5,6] Benzo [1,2-d] Thiazole-7-yl) -3-Methoxypropane-1,2-diamine was obtained (yield 75 mg). ..
1 H NMR (CDCl 3 ) δ (ppm) 7.01 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.04 (s, 2H), 5.82 (s, 1H), 4.04 (s, 1H), 3.55 --3.68 (m, 2H), 3.38 (s, 3H), 3.05 (dd, J = 13.0, 5.4 Hz, 1H), 2.97 (dd, J = 13.0, 5.7 Hz, 1H)
（第４工程）
Ｎ２－（［１，３］ジオキソロ［４’，５’：５，６］ベンゾ［１，２－ｄ］チアゾール－７－イル）－３－メトキシプロパン－１，２－ジアミン（７０ｍｇ，０．２５ｍｍｏｌ）を用い、実施例１の第５工程記載の方法と同様にして、表題化合物を得た（収量４７ｍｇ）。
1H NMR (DMSO-d6) δ (ppm) 7.85 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.07 - 6.14 (m, 2H), 4.70 - 4.80 (m, 1H), 3.85 - 3.95 (m, 1H), 3.60 - 3.72 (m, 2H), 3.37 - 3.46 (m, 1H), 3.28 (s, 3H); LCMS (m/z): 307.9 [M+H]+ (4th step)
N2- ([1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-yl) -3-methoxypropane-1,2-diamine (70 mg, 0. Using 25 mmol), the title compound was obtained (yield 47 mg) in the same manner as in the method described in the fifth step of Example 1.
1 H NMR (DMSO-d 6 ) δ (ppm) 7.85 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.07 --6.14 (m, 2H), 4.70 --4.80 (m, 1H), 3.85 --3.95 (m, 1H), 3.60 --3.72 (m, 2H), 3.37 --3.46 (m, 1H), 3.28 (s, 3H); LCMS (m / z): 307.9 [M + H] +
実施例４
（Ｓ）－１－（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）－５－（モルホリノメチル）イミダゾリジン－２－オンの製造
Figure JPOXMLDOC01-appb-C000019
 （第１工程）
　Ｄ－セリンメチル塩酸塩（４．９ｇ，３２ｍｍｏｌ）の無水ＤＣＭ溶液（２０ｍＬ）に、室温で３，４－ジヒドロ－２Ｈ－ピラン（４．０ｇ，４７ｍｍｏｌ）およびｐ－トルエンスルホン酸一水和物（０．３０ｇ，１．６ｍｍｏｌ）を加え、１日間撹拌した。反応混合物をろ過し、固体をＤＣＭで洗浄後、乾燥させて（２Ｒ）－２－アミノ－３－[（テトラヒドロ－２Ｈ－ピラン－２－イル）オキシ）]プロパン酸メチルを得た（収量５．０ｇ）。
1H NMR (DMSO-d6) δ (ppm) 8.56 (br. s, 3H), 4.55 - 4.66 (m, 1H), 4.39 (br. s, 1H), 4.01 (dd, J = 11.0, 3.9 Hz, 1H), 3.65 - 3.85 (m, 4H), 3.56 - 3.66 (m, 1H), 3.41 - 3.51 (m, 1H), 1.39 - 1.70 (m, 6H) Example 4
(S) Production of -1- (7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) -5- (morpholinomethyl) imidazolidine-2-one
Figure JPOXMLDOC01-appb-C000019
 (First step)
3,4-Dihydro-2H-pyran (4.0 g, 47 mmol) and p-toluenesulfonic acid monohydrate (20 mL) in anhydrous DCM solution (4.9 g, 32 mmol) of D-serine methyl hydrochloride (4.0 g, 47 mmol) at room temperature. 0.30 g, 1.6 mmol) was added, and the mixture was stirred for 1 day. The reaction mixture was filtered, the solid was washed with DCM and then dried to give methyl (2R) -2-amino-3-[(tetrahydro-2H-pyran-2-yl) oxy)] propanoate (yield 5). .0g).
1 H NMR (DMSO-d 6 ) δ (ppm) 8.56 (br. S, 3H), 4.55 --4.66 (m, 1H), 4.39 (br. S, 1H), 4.01 (dd, J = 11.0, 3.9 Hz) , 1H), 3.65 --3.85 (m, 4H), 3.56 --3.66 (m, 1H), 3.41 --3.51 (m, 1H), 1.39 --1.70 (m, 6H)
（第２工程）
　窒素雰囲気下、ＬＡＨ（１．５ｇ，４２ｍｍｏｌ）の無水ＴＨＦ溶液（６０ｍＬ）に、１（２Ｒ）－２－アミノ－３－[（テトラヒドロ－２Ｈ－ピラン－２－イル）オキシ]プロパン酸メチル（５．０ｇ，２１ｍｍｏｌ）の無水ＴＨＦ溶液（２０ｍＬ）を、氷冷で、２分間かけて滴下し、室温で３０分攪拌した後、２時間加熱還流した。反応溶液を氷冷後、水（６．４ｍL）及び１５％－水酸化ナトリウム水溶液（１．６ｍL）を加え、不溶物を濾過により取り除いた。ろ液を減圧濃縮し、粗精製の（２Ｓ）－２－アミノ－３－［（テトラヒドロ－２Ｈ－ピラン－２－イル）オキシ］プロパン－１－オールを得た（収量３．１ｇ）。 (Second step)
In an anhydrous THF solution (60 mL) of LAH (1.5 g, 42 mmol) under a nitrogen atmosphere, 1 (2R) -2-amino-3-[(tetrahydro-2H-pyran-2-yl) oxy] methyl propanoate ( An anhydrous THF solution (20 mL) of 5.0 g, 21 mmol) was added dropwise over 2 minutes on ice-cooled, stirred at room temperature for 30 minutes, and then heated and refluxed for 2 hours. After cooling the reaction solution with ice, water (6.4 mL) and a 15% -sodium hydroxide aqueous solution (1.6 mL) were added, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give crudely purified (2S) -2-amino-3-[(tetrahydro-2H-pyran-2-yl) oxy] propan-1-ol (yield 3.1 g).
（第３工程）
　（２Ｓ）－２－アミノ－３－［（テトラヒドロ－２Ｈ－ピラン－２－イル）オキシ］プロパン－１－オールから実施例１の第１工程記載の方法と同様にして得られた｛（２Ｓ）－１－ヒドロキシ－３－［（テトラヒドロ－２Ｈ－ピラン－２－イル）オキシ］プロパン－２－イル｝カルバミン酸　ｔｅｒｔ－ブチル（５．８ｇ，２１ｍｍｏｌ）のＴＨＦ溶液（６０ｍＬ）にフタルイミド（３．４ｇ，２３ｍｍｏｌ）、トリフェニルホスフィン（７．１ｇ，２７ｍｍｏｌ）を加え、次いでジエチルアゾジカルボキシレート（２．２Ｍトルエン溶液，５．４ｍＬ，２５ｍｍｏｌ）のＴＨＦ溶液（２０ｍＬ）を室温でゆっくり添加した。混合液を１日間攪拌後、反応溶液を水で希釈し、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去後、残渣をカラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）で精製し、粗精製のｔｅｒｔ－ブチル｛（２Ｓ）－１－（１，３－ジオキソイソインドリン－２－イル）－３－［（テトラヒドロ－２Ｈ－ピラン－２－イル）オキシ］－２－プロピニル｝カーバメートを得た（収量８．５ｇ）。 (Third step)
(2S) -2-Amino-3-[(tetrahydro-2-H-pyran-2-yl) oxy] Propan-1-ol obtained in the same manner as in the method described in the first step of Example 1 {(2S) ) -1-Hydroxy-3-[(tetrahydro-2H-pyran-2-yl) oxy] propan-2-yl} tert-butyl carbamic acid (5.8 g, 21 mmol) in THF solution (60 mL) with phthalimide (3) .4 g, 23 mmol), triphenylphosphine (7.1 g, 27 mmol) was added, then a THF solution (20 mL) of diethylazodicarboxylate (2.2 M toluene solution, 5.4 mL, 25 mmol) was slowly added at room temperature. .. After stirring the mixture for 1 day, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue is purified by column chromatography (silica gel, hexane / ethyl acetate) and crudely purified tert-butyl {(2S) -1- (1,3-dioxoisoindoline-2-yl). ) -3-[(Tetrahydro-2H-pyran-2-yl) oxy] -2-propinyl} carbamate was obtained (yield 8.5 g).
（第４工程）
　ｔｅｒｔ－ブチル｛（２Ｓ）－１－（１，３－ジオキソイソインドリン－２－イル）－３－［（テトラヒドロ－２Ｈ－ピラン－２－イル）オキシ］－２－プロピニル｝カーバメートを塩酸で処理して得られた（Ｓ）－２－（２－アミノ－３－ヒドロキシプロピル）イソインドリン－１，３－ジオン（２．７ｇ，１０．５ｍｍｏｌ）のエタノール溶液（１０ｍＬ）に、参考例３で得られた４－イソチオシアネート－２，３－ジヒドロベンゾフラン（１．４ｇ，８ｍｍｏｌ）およびナトリウムエトキシド（４．４ｇ，６４．４ｍｍｏｌ）を加え、４０℃で１８時間撹拌した。反応溶液を水で希釈し、酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去後、残渣をカラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）で精製し、（Ｓ）－１－（２，３－ジヒドロベンゾフラン－４－イル）－３－［１－（１，３－ジオキソイソインドリン－２－イル）－３－ヒドロキシプロパン－２－イル］チオウレアを得た（収量０．７ｇ）。
1H NMR (400 MHz, CDCl3) δ 7.91 - 7.70 (m, 4H), 7.39 (s, 1H), 7.30 - 7.15 (m, 1H), 6.81 - 6.72 (m, 2H), 6.62 (d, J = 8.3 Hz, 1H), 4.91 (s, 1H), 4.68 - 4.53 (m, 2H), 4.17 - 4.04 (m, 1H), 3.84 - 3.69 (m, 3H), 3.15 (t, J = 8.7 Hz, 2H), 2.51 (t, J = 6.1 Hz, 1H). (4th step)
tert-butyl {(2S) -1- (1,3-dioxoisoindoline-2-yl) -3-[(tetrahydro-2H-pyran-2-yl) oxy] -2-propinyl} carbamate with hydrochloric acid Reference Example 3 was added to the ethanol solution (10 mL) of (S) -2- (2-amino-3-hydroxypropyl) isoindoline-1,3-dione (2.7 g, 10.5 mmol) obtained by the treatment. 4-Isothiocyanate-2,3-dihydrobenzofuran (1.4 g, 8 mmol) and sodium ethoxydo (4.4 g, 64.4 mmol) obtained in the above were added, and the mixture was stirred at 40 ° C. for 18 hours. The reaction solution was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, hexane / ethyl acetate), and (S) -1- (2,3-dihydrobenzofuran-4-yl) -3- [1- (1). , 3-Dioxoisoindoline-2-yl) -3-hydroxypropane-2-yl] Thiourea was obtained (yield 0.7 g).
1 H NMR (400 MHz, CDCl 3 ) δ 7.91 --7.70 (m, 4H), 7.39 (s, 1H), 7.30 --7.15 (m, 1H), 6.81 --6.72 (m, 2H), 6.62 (d, J) = 8.3 Hz, 1H), 4.91 (s, 1H), 4.68 --4.53 (m, 2H), 4.17 --4.04 (m, 1H), 3.84 --3.69 (m, 3H), 3.15 (t, J = 8.7 Hz, 2H), 2.51 (t, J = 6.1 Hz, 1H).
（第５工程）
　（Ｓ）－１－（２，３－ジヒドロベンゾフラン－４－イル）－３－［１－（１，３－ジオキソイソインドリン－２－イル）－３－ヒドロキシプロパン－２－イル］チオウレア（０．７ｇ，１．７６ｍｍｏｌ）のアセトニトリル溶液（２５ｍＬ）に、酢酸（０．５ｍＬ，８。８ｍｍｏｌ）および臭素（９１μｌ，１．７６ｍｍｏｌ）を加え、氷冷下、３０分間撹拌した。反応溶液を２規定水酸化ナトリウム水溶液で希釈し、酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去し、粗精製の（（Ｓ）－２－｛２－［（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）アミノ］－３－ヒドロキシプロピル｝イソインドリン－１，３－ジオンを得た（収量０．７ｇ）。 (Fifth step)
(S) -1- (2,3-dihydrobenzofuran-4-yl) -3- [1- (1,3-dioxoisoindoline-2-yl) -3-hydroxypropane-2-yl] thiourea ( Acetic acid (0.5 mL, 8.8 mmol) and bromine (91 μl, 1.76 mmol) were added to an acetonitrile solution (25 mL) of 0.7 g, 1.76 mmol, and the mixture was stirred for 30 minutes under ice-cooling. The reaction solution was diluted with 2N aqueous sodium hydroxide solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crudely purified ((S) -2-{2-[(7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) amino] -3-hydroxypropyl} was used. Isoindoline-1,3-dione was obtained (yield 0.7 g).
（第６工程）
　（Ｓ）－２－｛２－［（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）アミノ］－３－ヒドロキシプロピル｝イソインドリン－１，３－ジオン（０．７０ｇ，１．８ｍｍｏｌ）のＤＭＦ溶液（１５ｍＬ）に、室温でイミダゾール（０．１８ｇ，２．６ｍｍｏｌ）およびｔｅｒｔ－ブチルジメチルクロロシラン（０．３５ｇ，２．３ｍｍｏｌ）を加え、２時間撹拌した。反応溶液を水で希釈し、酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去後、残渣をカラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）で精製し、（Ｓ）－２－｛３－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］－２－［（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）アミノ］プロピル｝イソインドリン－１，３－ジオンを得た（収量０．７２ｇ）。
1H NMR (CDCl3) δ (ppm) 7.73 - 7.81 (m, 2H), 7.59 - 7.69 (m, 2H), 7.14 - 7.21 (m, 1H), 6.53 (d, J = 8.3 Hz, 1H), 5.67 (d, J = 8.9 Hz, 1H), 4.48 - 4.64 (m, 2H), 4.33 - 4.38 (m, 1H), 4.02 - 4.17 (m, 1H), 3.80 - 4.01 (m, 3H), 3.10 - 3.36 (m, 2H), 0.93 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H) ; LCMS (m/z): 510.2 [M+H]+ (6th step)
(S) -2-{2-[(7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) amino] -3-hydroxypropyl} isoindoline-1,3-dione (0. Imidazole (0.18 g, 2.6 mmol) and tert-butyldimethylchlorosilane (0.35 g, 2.3 mmol) were added to a DMF solution (15 mL) of 70 g, 1.8 mmol at room temperature, and the mixture was stirred for 2 hours. The reaction solution was diluted with water, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography (silica gel, hexane / ethyl acetate), and (S) -2-{3-[(tert-butyldimethylsilyl) oxy] -2-[(7, 8-Dihydrobenzoflo [4,5-d] thiazole-2-yl) amino] propyl} isoindoline-1,3-dione was obtained (yield 0.72 g).
1 H NMR (CDCl 3 ) δ (ppm) 7.73 --7.81 (m, 2H), 7.59 --7.69 (m, 2H), 7.14 --7.21 (m, 1H), 6.53 (d, J = 8.3 Hz, 1H), 5.67 (d, J = 8.9 Hz, 1H), 4.48 --4.46 (m, 2H), 4.33 --4.38 (m, 1H), 4.02 --4.17 (m, 1H), 3.80 --4.01 (m, 3H), 3.10- 3.36 (m, 2H), 0.93 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); LCMS (m / z): 510.2 [M + H] +
（第７工程）
　（Ｓ）－２－｛３－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］－２－［（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）アミノ］プロピル｝イソインドリン－１，３－ジオン（０．７２ｇ，１．４ｍｍｏｌ）をＴＨＦ－メタノール１：１の混合溶媒（６．０ｍＬ）に溶解し、次いでヒドラジン一水和物（０．６８ｍＬ，１４ｍｍｏｌ）を加え、５０℃で３時間攪拌した。反応液をセライトろ過した後にろ液を濃縮し、残渣を酢酸エチルに溶解した。これを飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去して、粗精製の（Ｓ）－３－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］－Ｎ２－（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）プロパン－１，２－ジアミンを得た（収量０．５４ｇ）。
1H NMR (CDCl3) δ (ppm) 7.25 - 7.33 (m, 1H), 6.62 (d, J = 8.3 Hz, 1H), 5.84 (d, J = 8.8 Hz, 1H), 4.64 (t, J = 8.7 Hz, 2H), 3.86 (dd, J = 10.1, 3.3 Hz, 1H), 3.74 - 3.79 (m, 1H), 3.69 (br. s, 1H), 3.36 - 3.45 (m, 2H), 2.90 - 3.09 (m, 2H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H) (7th step)
(S) -2-{3-[(tert-butyldimethylsilyl) oxy] -2-[(7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) amino] propyl} isoindoline -1,3-Dione (0.72 g, 1.4 mmol) is dissolved in a mixed solvent of THF-methanol 1: 1 (6.0 mL), then hydrazine monohydrate (0.68 mL, 14 mmol) is added. The mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was filtered through cerite, the filtrate was concentrated, and the residue was dissolved in ethyl acetate. This was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain crude (S) -3-[(tert-butyldimethylsilyl) oxy] -N2- (7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl). ) Propane-1,2-diamine was obtained (yield 0.54 g).
1 H NMR (CDCl 3 ) δ (ppm) 7.25 --7.33 (m, 1H), 6.62 (d, J = 8.3 Hz, 1H), 5.84 (d, J = 8.8 Hz, 1H), 4.64 (t, J = 8.7 Hz, 2H), 3.86 (dd, J = 10.1, 3.3 Hz, 1H), 3.74 --3.79 (m, 1H), 3.69 (br. S, 1H), 3.36 --3.45 (m, 2H), 2.90 --3.09 (m, 2H), 0.90 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H)
（第８工程）
（Ｓ）－３－［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］－Ｎ２－（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）プロパン－１，２－ジアミン（０．５４ｇ，１．４ｍｍｏｌ）を用い、実施例１の第５工程記載の方法と同様にして、（Ｓ）－５－｛［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］メチル｝－１－（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）イミダゾリジン－２－オンを得た（収量０．５７ｇ）。
1H NMR (CDCl3) δ 7.45 - 7.37 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.86 (s, 1H), 4.78 - 4.67 (m, 1H), 4.62 (t, J = 8.8 Hz, 2H), 4.11 - 3.92 (m, 2H), 3.73 - 3.60 (m, 2H), 3.46 - 3.32 (m, 2H), 0.82 (s, 9H), -0.07 (d, J = 0.8 Hz, 6H). (8th step)
(S) -3-[(tert-butyldimethylsilyl) oxy] -N2- (7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) propane-1,2-diamine (0. (54 g, 1.4 mmol) was used in the same manner as in the method described in the fifth step of Example 1, (S) -5-{[(tert-butyldimethylsilyl) oxy] methyl} -1- (7,8). -Dihydrobenzoflo [4,5-d] thiazole-2-yl) imidazolidine-2-one was obtained (yield 0.57 g).
1 1 H NMR (CDCl 3 ) δ 7.45 --7.37 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 4.86 (s, 1H), 4.78 --4.67 (m, 1H), 4.62 (t, J) = 8.8 Hz, 2H), 4.11 --3.92 (m, 2H), 3.73 --3.60 (m, 2H), 3.46 --3.32 (m, 2H), 0.82 (s, 9H), -0.07 (d, J = 0.8 Hz) , 6H).
（第９工程）
　（Ｓ）－５－｛［（ｔｅｒｔ－ブチルジメチルシリル）オキシ］メチル｝－１－（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）イミダゾリジン－２－オン（０．５７ｇ，１．４ｍｍｏｌ）のＴＨＦ溶液（１１ｍＬ）に、室温でテトラブチルアンモニウムフルオリド（１．０Ｍ ＴＨＦ溶液，２．８ｍＬ，２．８ｍｍｏｌ）を加え、３０分間撹拌した。反応溶液を水で希釈し、酢酸エチルで抽出後、有機層を無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去後、乾燥させて粗精製の（Ｓ）－１－（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）－５－（ヒドロキシメチル）イミダゾリジン－２－オンを得た（収量０．３３ｇ）。
1H NMR (DMSO-d6) δ (ppm) 7.76 (br. s, 1H), 7.54 - 7.61 (m, 1H), 6.73 (d, J = 8.3 Hz, 1H), 5.12 (t, J = 5.7 Hz, 1H), 4.56 - 4.69 (m, 3H), 3.90 - 4.01 (m, 1H), 3.68 - 3.75 (m, 1H), 3.62 (t. J -= 10.0 Hz, 1H), 3.41 - 3.48 (m, 1H), 3.36 (t. J -= 8.0 Hz, 2H) ; LCMS (m/z): 292.1 [M+H]+ (9th step)
(S) -5-{[(tert-butyldimethylsilyl) oxy] methyl} -1- (7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) imidazolidine-2-one ( Tetrabutylammonium fluoride (1.0 M THF solution, 2.8 mL, 2.8 mmol) was added to a THF solution (11 mL) of 0.57 g, 1.4 mmol) at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, it is dried and crudely purified (S) -1- (7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) -5- (hydroxymethyl) imidazolidine-. 2-On was obtained (yield 0.33 g).
1 H NMR (DMSO-d 6 ) δ (ppm) 7.76 (br. S, 1H), 7.54 --7.61 (m, 1H), 6.73 (d, J = 8.3 Hz, 1H), 5.12 (t, J = 5.7) Hz, 1H), 4.56 --4.69 (m, 3H), 3.90 --4.01 (m, 1H), 3.68 --3.75 (m, 1H), 3.62 (t. J-= 10.0 Hz, 1H), 3.41 --3.48 (m) , 1H), 3.36 (t. J-= 8.0 Hz, 2H); LCMS (m / z): 292.1 [M + H] +
（第１０工程）
　（Ｓ）－１－（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）－５－（ヒドロキシメチル）イミダゾリジン－２－オン（０．３ｇ，１．０６ｍｍｏｌ）のＴＨＦ溶液（１５ｍＬ）に、氷冷下、メタンスルホニルクロリド（０．１７ｍＬ，２．１ｍｍｏｌ）およびＴＥＡ（０．４５ｍＬ，３．２ｍｍｏｌ）を加え、０℃で３０分間攪拌した。反応溶液を炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去して、粗精製のメタンスルホン酸（Ｓ）－［３－（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）－２－オキソイミダゾリジン－４－イル］メチルを得た（収量０．３４ｇ）。 (10th step)
(S) -1- (7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) -5- (hydroxymethyl) imidazolidine-2-one (0.3 g, 1.06 mmol) Methanesulfonyl chloride (0.17 mL, 2.1 mmol) and TEA (0.45 mL, 3.2 mmol) were added to a THF solution (15 mL) under ice-cooling, and the mixture was stirred at 0 ° C. for 30 minutes. The reaction solution was diluted with an aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. Distilling off the solvent under reduced pressure, crudely purified methanesulfonic acid (S)-[3- (7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) -2-oxoimidazolidine-4. -Il] Methyl was obtained (yield 0.34 g).
（第１１工程）
　メタンスルホン酸（Ｓ）－［３－（７，８－ジヒドロベンゾフロ［４，５－ｄ］チアゾール－２－イル）－２－オキソイミダゾリジン－４－イル］メチル（９２ｍｇ，０．２５ｍｍｏｌ）のアセトニトリル溶液（３ｍＬ）に、モルホリン（０．２２ｍｇ，２．５ｍｍｏｌ）およびＴＥＡ（０．３５ｍＬ，２．５ｍｍｏｌ）を加え、７０℃で１８時間攪拌した。反応溶液を炭酸水素ナトリウム水溶液で希釈し、酢酸エチルで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。溶媒を減圧留去し、得られた残渣をＨＰＬＣ分取システムを用いて精製し、表題化合物を得た（収量３０ｍｇ）。
1H NMR (CDCl3) δ (ppm) 7.48 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.82 - 4.91 (m, 2H), 4.69 (d, J = 8.0 Hz, 2H), 3.59 - 3.82 (m, 6H), 3.45 (t, J = 8.7 Hz, 2H), 3.01 - 3.10 (m, 1H), 2.67 - 2.76 (m, 2H), 2.57 - 2.67 (m, 1H), 2.46 - 2.56 (m, 2H) ; LCMS (m/z): 361.2 [M+H]+ (11th step)
Methanesulfonic acid (S)-[3- (7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) -2-oxoimidazolidine-4-yl] methyl (92 mg, 0.25 mmol) Morpholine (0.22 mg, 2.5 mmol) and TEA (0.35 mL, 2.5 mmol) were added to the acetonitrile solution (3 mL), and the mixture was stirred at 70 ° C. for 18 hours. The reaction solution was diluted with an aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified using an HPLC preparative system to obtain the title compound (yield 30 mg).
1 H NMR (CDCl 3 ) δ (ppm) 7.48 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.82 --4.91 (m, 2H), 4.69 (d, J = 8.0 Hz, 2H), 3.59 --3.82 (m, 6H), 3.45 (t, J = 8.7 Hz, 2H), 3.01 --3.30 (m, 1H), 2.67 --2.76 (m, 2H), 2.57 --2.67 (m) , 1H), 2.46 --2.56 (m, 2H); LCMS (m / z): 361.2 [M + H] +
　以下の実施例化合物［表１］は、それぞれ対応する原料（市販品、または市販化合物から公知の方法もしくはそれに準じた方法により誘導体化した化合物）を用い、上述の実施例記載の方法に従い、必要に応じて、有機合成化学で通常用いられる方法を適宜組み合わせて製造した。また、各々の化合物の物理化学データを［表２］に示した。
　表中、実施例２３ａ、２３ｂ、２４ａ、２４ｂ、２５ａ、２５ｂ、４９ａ、４９ｂ、５５ａ、５５ｂ、５８ａ、５８ｂ、５９ａ、５９ｂ、８３ａおよび８３ｂは、光学活性中心の置換基の置換位置についてＲ体またはＳ体いずれかの立体異性体であることを示す。また、これらは光学分割により単一の化合物として取得した化合物を表す。 The following Example compounds [Table 1] are required according to the above-mentioned method described in Examples, using the corresponding raw materials (commercially available products or compounds derivatized from commercially available compounds by a known method or a method similar thereto). Therefore, it was produced by appropriately combining the methods usually used in synthetic organic chemistry. The physicochemical data of each compound are shown in [Table 2].
In the table, Examples 23a, 23b, 24a, 24b, 25a, 25b, 49a, 49b, 55a, 55b, 58a, 58b, 59a, 59b, 83a and 83b are R-forms with respect to the substitution position of the substituent of the optically active center. Alternatively, it indicates that it is a stereoisomer of any of the S-forms. Further, these represent compounds obtained as a single compound by optical resolution.
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000088
　試験例１ Test example 1
［ＤＹＲＫファミリー（ＤＹＲＫ１Ａ、ＤＹＲＫ１Ｂ、ＤＹＲＫ２、ＤＹＲＫ３）に対する活性阻害試験］
（キナーゼ活性の測定方法）
　キナーゼ活性の測定は、ＱｕｉｃｋＳｃｏｕｔ Ｓｃｒｅｅｎｉｎｇ Ａｓｓｉｓｔ（商標）ＭＳＡ（カルナバイオサイエンス社製市販キット）を用い、モビリティシフトアッセイ（ＭＳＡ）法により行った。キナーゼ反応の基質は、キット付属のＦＩＴＣ標識ＤＹＲＫｔｉｄｅペプチドを用いた。アッセイバッファー［２０ｍＭ ＨＥＰＥＳ、０．０１％Ｔｒｉｔｏｎ Ｘ-１００（商標）、２ｍＭ ｄｉｔｈｉｏｔｈｒｅｉｔｏｌ、ｐＨ７．５］を用い、基質（４μＭ）、ＭｇＣｌ２（２０ｍＭ）およびＡＴＰ（ＤＹＲＫ１Ａ；１００μＭ、ＤＹＲＫ１Ｂ；２００μＭ、ＤＹＲＫ２；４０μＭ、ＤＹＲＫ３；２０μＭ）の基質混合液を作成した。また、キナーゼ（ＤＹＲＫ１Ａ；カルナバイオサイエンス社製、カタログＮｏ．０４－１３０、ＤＹＲＫ１Ｂ、同社製、Ｎｏ．０４－１３１、ＤＹＲＫ２；同社製、Ｎｏ．０４－１３２、ＤＹＲＫ３；同社製、Ｎｏ．０４－１３３）をアッセイバッファーで希釈して酵素溶液（ＤＹＲＫ１Ａ；０．２ｎｇ/μＬ、ＤＹＲＫ１Ｂ；０．０８ｎｇ/μＬ、ＤＹＲＫ２；０．０４ｎｇ/μＬ、ＤＹＲＫ３；０．２５ｎｇ/μＬ）を調製した。被験化合物の１０ｍＭ ＤＭＳＯ溶液から、１０濃度（０．００００３ｍＭ、０．０００１ｍＭ、０．０００３ｍＭ、０．００１ｍＭ、０．００３ｍＭ、０．０１ｍＭ、０．０３ｍＭ、０．１ｍＭ、０．３ｍＭ、１ｍＭ）にＤＭＳＯでさらに希釈し、それぞれをアッセイバッファーで２５倍希釈して、薬物溶液とした（４％ＤＭＳＯ溶液）。薬物溶液もしくはコントロール溶液（４％ＤＭＳＯ－アッセイバッファー）５μＬ、基質混合液５μＬ、および酵素溶液１０μＬをポリプロピレン製３８４穴プレートのウェル中で混合し、１時間室温で反応させた後、６０μＬのキット付属のターミネーションバッファーを添加し反応を停止させた。ついで、反応溶液中の、基質（Ｓ）およびリン酸化された基質（Ｐ）の量をＬａｂＣｈｉｐ ＥＺ Ｒｅａｄｅｒ ＩＩシステム（Ｃａｌｉｐｅｒ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ社製）を用い、アッセイキットのプロトコールにしたがって測定した。 [Activity inhibition test for DYRK family (DYRK1A, DYRK1B, DYRK2, DYRK3)]
(Measuring method of kinase activity)
Kinase activity was measured by the Mobility Shift Assay (MSA) method using QuickScout Screening Assay ™ MSA (commercially available kit from Carna Biosciences). The substrate for the kinase reaction was the FITC-labeled DYRKtide peptide included in the kit. Using assay buffer [20 mM HEPES, 0.01% Triton X-100 ™, 2 mM dithiothreitol, pH 7.5], substrate (4 μM), MgCl 2 (20 mM) and ATP (DYRK1A; 100 μM, DYRK1B; 200 μM, DYRK2). A substrate mixture of 40 μM, DYRK3; 20 μM) was prepared. In addition, kinase (DYRK1A; manufactured by Carna Biosciences, Catalog No. 04-130, DYRK1B, manufactured by the same company, No. 04-131, DYRK2; manufactured by the same company, No. 04-132, DYRK3; manufactured by the same company, No. 04- 133) was diluted with an assay buffer to prepare an enzyme solution (DYRK1A; 0.2 ng / μL, DYRK1B; 0.08 ng / μL, DYRK2; 0.04 ng / μL, DYRK3; 0.25 ng / μL). From a 10 mM DMSO solution of the test compound to 10 concentrations (0.00003 mM, 0.0001 mM, 0.0003 mM, 0.001 mM, 0.003 mM, 0.01 mM, 0.03 mM, 0.1 mM, 0.3 mM, 1 mM) It was further diluted with DMSO and each was diluted 25-fold with assay buffer to give a drug solution (4% DMSO solution). 5 μL of drug or control solution (4% DMSO-assay buffer), 5 μL of substrate mixture, and 10 μL of enzyme solution are mixed in wells of a 384-well polypropylene plate and reacted at room temperature for 1 hour before being included in the 60 μL kit. The termination buffer of No. 1 was added to stop the reaction. The amount of substrate (S) and phosphorylated substrate (P) in the reaction solution was then measured using the LabChip EZ Reader II system (Caliper Life Sciences) according to the assay kit protocol.
（阻害活性の評価方法）
　「基質」および「リン酸化された基質」の各ピークの高さをそれぞれＳおよびＰとし、またブランクとして酵素溶液の代わりにアッセイバッファーを添加したものを測定した。 (Evaluation method of inhibitory activity)
The heights of the peaks of the "substrate" and the "phosphorylated substrate" were S and P, respectively, and the blanks were measured with the assay buffer added instead of the enzyme solution.
　被験化合物の阻害率（％）は、次の式に従って算出した。
阻害率（％）＝（１－（Ｃ－Ａ）／（Ｂ－Ａ））×１００
ただし、Ａ、Ｂ、Ｃは、それぞれブランクウェルのＰ／（Ｐ＋Ｓ）、コントロール溶液ウェルのＰ／（Ｐ＋Ｓ）、化合物添加ウェルのＰ／（Ｐ＋Ｓ）を示す。 The inhibition rate (%) of the test compound was calculated according to the following formula.
Inhibition rate (%) = (1- (CA) / (BA)) × 100
However, A, B, and C indicate P / (P + S) of the blank well, P / (P + S) of the control solution well, and P / (P + S) of the compound-added well, respectively.
　また、ＩＣ５０値は、阻害率と被験化合物濃度（対数）の回帰分析により算出した。
（評価結果）
　本発明の代表化合物のＤＹＲＫ１Ａ、ＤＹＲＫ１Ｂ、ＤＹＲＫ２、ＤＹＲＫ３に対する阻害活性を表３に示す。キナーゼ活性阻害作用はＩＣ５０値が、０．０１μＭ未満を＊＊＊印、０．０１μＭ以上０．１μＭ未満を＊＊印、０．１μＭ以上１μＭ未満を＊印、１μＭ以上を－で示した。 The IC50 value was calculated by regression analysis of the inhibition rate and the test compound concentration (logarithm).
(Evaluation results)
Table 3 shows the inhibitory activity of the representative compound of the present invention on DYRK1A, DYRK1B, DYRK2 and DYRK3. Kinase activity inhibitory effects are indicated by *** marks when the IC50 value is less than 0.01 μM, ** marks when 0.01 μM or more and less than 0.1 μM, * marks when 0.1 μM or more and less than 1 μM, and-when 1 μM or more. ..
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095


　この結果は、被験化合物（本発明化合物（Ｉ））が、強いＤＹＲＫ阻害活性を有することを示している。
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095


This result indicates that the test compound (compound (I) of the present invention) has a strong DYRK inhibitory activity.
　本発明により提供される化合物は、ＤＹＲＫ１Ａを介した異常な細胞応答に関連していることが知られている疾患、例えば、アルツハイマー病、パーキンソン病、ダウン症、精神遅滞、記憶障害、記憶喪失、鬱病のような精神・神経疾患、さらに脳腫瘍などの癌に対する予防または治療剤として有用である。またＤＹＲＫ１Ｂの阻害剤として、膵臓癌などの癌に対する予防または治療用医薬品（医薬組成物）として有用である。さらに本発明により提供される化合物は、ＤＹＲＫ２については、ＤＮＡ損傷に応答してｐ５３を制御し、アポトーシスを誘導することから、骨吸収疾患および骨粗鬆症に対する予防または治療用医薬品（医薬組成物）として有用である。また本発明により提供される化合物は、ＤＹＲＫ３の阻害剤として、鎌状赤血球貧血、慢性腎疾患、骨吸収疾患および骨粗鬆症に対する予防または治療用医薬品（医薬組成物）として有用である。また、ＤＹＲＫを阻害する化合物として、上記の疾患に関する病態イメージングの試薬や基礎実験用、研究用の試薬に有用である。 The compounds provided by the present invention are diseases known to be associated with DYRK1A-mediated abnormal cellular responses, such as Alzheimer's disease, Parkinson's disease, Down's disease, mental retardation, memory impairment, memory loss, depression. It is useful as a preventive or therapeutic agent for mental and neurological diseases such as, as well as cancers such as brain tumors. Further, as an inhibitor of DYRK1B, it is useful as a prophylactic or therapeutic drug (pharmaceutical composition) for cancers such as pancreatic cancer. Furthermore, the compound provided by the present invention is useful as a prophylactic or therapeutic drug (pharmaceutical composition) for bone resorption disease and osteoporosis because it controls p53 in response to DNA damage and induces apoptosis of DYRK2. Is. Further, the compound provided by the present invention is useful as an inhibitor of DYRK3 as a prophylactic or therapeutic drug (pharmaceutical composition) for sickle cell anemia, chronic kidney disease, bone resorption disease and osteoporosis. Further, as a compound that inhibits DYRK, it is useful as a reagent for pathological imagery related to the above-mentioned diseases and a reagent for basic experiments and research.

Claims (18)

  1. 下式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     （式中、Ａ１は酸素原子、窒素原子（＝Ｎ－）またはＮＲＡを表し、
    Ａ２はＣＲＢ、ＣＲＣＲＤ、酸素原子、窒素原子（＝Ｎ－）またはＮＲＡを表し、
    ＲＡ、ＲＢ、ＲＣおよびＲＤは、それぞれ独立して、水素原子またはＣ１－６アルキル基を表し、
    Ｌは、リンカーであって、炭素数１または２の炭素リンカー、窒素原子（＝Ｎ－）またはＮＲＡを表し、
    ここにおいて、Ａ１とＡ２はそれぞれ結合する芳香環およびリンカーＬと一緒になって、飽和もしくは不飽和の三環性縮合環を形成し、
    Ｒ1は、水素原子、置換基を有してもよいアルキル基、置換基を有してもよいアルケニル基、置換基を有してもよいシクロアルキル基、置換基を有してもよいアリール基、置換基を有してもよいヘテロアリール基、置換基を有してもよい飽和複素環基を表し、
    Ｒ２は、水素原子またはメチル基を表す。）
    で示される環状ウレア誘導体またはその薬学的に許容される塩。     Equation (I):
    Figure JPOXMLDOC01-appb-C000001
     (In the formula, A 1 represents an oxygen atom, a nitrogen atom (= N-) or NRA, and represents
    A 2 represents CR B , CR C R D , oxygen atom, nitrogen atom (= N-) or NR A.
    RA , RB, RC and RD each independently represent a hydrogen atom or a C 1-6 alkyl group.
    L is a linker and represents a carbon linker having 1 or 2 carbon atoms, a nitrogen atom (= N−) or NRA .
    Here, A 1 and A 2 together with the bonded aromatic ring and linker L form a saturated or unsaturated tricyclic condensed ring, respectively.
    R 1 is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, and an aryl which may have a substituent. Represents a group, a heteroaryl group which may have a substituent, and a saturated heterocyclic group which may have a substituent.
    R 2 represents a hydrogen atom or a methyl group. )
    A cyclic urea derivative or a pharmaceutically acceptable salt thereof.
  2. 　Ａ１およびＡ２がいずれも酸素原子であり、Ｌが－（ＣＨ２）－である、請求項１に記載の環状ウレア誘導体またはその薬学的に許容される塩。 The cyclic urea derivative according to claim 1, wherein A 1 and A 2 are both oxygen atoms and L is-(CH 2 )-, or a pharmaceutically acceptable salt thereof.
  3. 　Ａ１が酸素原子であり、ＬおよびＡ２がいずれも－（ＣＨ２）－である、請求項１に記載の環状ウレア誘導体またはその薬学的に許容される塩。 The cyclic urea derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A 1 is an oxygen atom and L and A 2 are both − (CH 2 ) −.
  4. 　Ｒ1が、水素原子、置換基を有してもよいＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ３－６シクロアルキル基、置換基を有してもよいフェニル基または置換基を有してもよいピリジル基を表す、請求項１～３のいずれかに記載の環状ウレア誘導体またはその薬学的に許容される塩。 R 1 is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, a phenyl group or a substituent which may have a substituent. The cyclic urea derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which represents a pyridyl group which may have.
  5. 　Ｒ1が、-ＣＨ２ＮＲ３Ｒ４または-ＣＨ２ＯＲ５で表され、
    　Ｒ３、Ｒ４は、それぞれ独立して、水素原子、Ｃ１－６アルキル基（ヒドロキシ基でさらに置換されていてもよい）、Ｃ2－６アルキニル基、Ｃ2－６アルケニル基、Ｃ３－６シクロアルキル基、Ｃ１－６アシル基（ヒドロキシ基でさらに置換されていてもよい）、メタンスルホニル基またはシアノメチル基を表し、あるいは、Ｒ３とＲ４はそれらが結合する窒素原子と一緒になり、１～２個の酸素原子、硫黄原子（スルホキシド、スルホンを含む）、ケイ素原子またはリン原子を含んでもよい、置換基を有することのある、４員から１０員の単環性もしくは二環性の飽和環状アミノ基を形成してもよく、
    　Ｒ５は、水素原子、Ｃ１－４アルキル基およびベンジル基から選択される、
    請求項４に記載の環状ウレア誘導体またはその薬学的に許容される塩。     R 1 is represented by -CH 2 NR 3 R 4 or -CH 2 OR 5 .
    R 3 and R 4 are independently hydrogen atom, C 1-6 alkyl group (may be further substituted with hydroxy group), C 2-6 alkynyl group, C 2-6 alkenyl group, C 3 Represents a -6 cycloalkyl group, a C 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 together with the nitrogen atom to which they are attached. May contain 1 to 2 oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms, and may have substituents, 4 to 10 member monocyclic or two. A cyclic saturated cyclic amino group may be formed,
    R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
    The cyclic urea derivative according to claim 4 or a pharmaceutically acceptable salt thereof.
  6. 　Ｒ1が置換基を有してもよいフェニル基またはピリジル基であり、当該置換基が、ハロゲン原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基である、請求項４に記載の環状ウレア誘導体またはその薬学的に許容される塩。 R 1 is a phenyl group or a pyridyl group which may have a substituent, and the substituent is selected from the group consisting of a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and a hydroxymethyl group. The cyclic urea derivative according to claim 4, which is a group of 3 substituents, or a pharmaceutically acceptable salt thereof.
  7. 　下式（Ｉ’）
    Figure JPOXMLDOC01-appb-C000002
     〔式中、Ａ１、Ａ２、Ｌ、Ｒ１、Ｒ２は上記（Ｉ）に同じ〕
    で示される、請求項１に記載の環状ウレア誘導体またはその薬学的に許容される塩。     The following formula (I')
    Figure JPOXMLDOC01-appb-C000002
     [In the formula, A 1 , A 2 , L, R 1 , and R 2 are the same as (I) above]
    The cyclic urea derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
  8. 　Ａ１およびＡ２がいずれも酸素原子であり、Ｌが－（ＣＨ２）－である、請求項７に記載の環状ウレア誘導体またはその薬学的に許容される塩。 The cyclic urea derivative according to claim 7, wherein A 1 and A 2 are both oxygen atoms and L is-(CH 2 )-, or a pharmaceutically acceptable salt thereof.
  9. 　Ａ１が酸素原子であり、ＬおよびＡ２がいずれも－（ＣＨ２）－である、請求項７に記載の環状ウレア誘導体またはその薬学的に許容される塩。 The cyclic urea derivative according to claim 7, or a pharmaceutically acceptable salt thereof, wherein A 1 is an oxygen atom and L and A 2 are both − (CH 2 ) −.
  10. 　Ｒ1が、水素原子、置換基を有してもよいＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ３－６シクロアルキル基、置換基を有してもよいフェニル基または置換基を有してもよいピリジル基を表す、請求項７～９のいずれかに記載の環状ウレア誘導体またはその薬学的に許容される塩。 R 1 is a hydrogen atom, a C 1-6 alkyl group which may have a substituent, a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, a phenyl group or a substituent which may have a substituent. The cyclic urea derivative according to any one of claims 7 to 9, or a pharmaceutically acceptable salt thereof, which represents a pyridyl group which may have.
  11. 　Ｒ1が、-ＣＨ２ＮＲ３Ｒ４または-ＣＨ２ＯＲ５で表され、
    　Ｒ３、Ｒ４は、それぞれ独立して、水素原子、Ｃ１－６アルキル基（ヒドロキシ基でさらに置換されていてもよい）、Ｃ2－６アルキニル基、Ｃ2－６アルケニル基、Ｃ３－６シクロアルキル基、Ｃ１－６アシル基（ヒドロキシ基でさらに置換されていてもよい）、メタンスルホニル基またはシアノメチル基を表し、あるいは、Ｒ３とＲ４はそれらが結合する窒素原子と一緒になり、１～２個の酸素原子、硫黄原子（スルホキシド、スルホンを含む）、ケイ素原子またはリン原子を含んでもよい、置換基を有することのある、４員から１０員の単環性もしくは二環性の飽和環状アミノ基を形成してもよく、
    　Ｒ５は、水素原子、Ｃ１－４アルキル基およびベンジル基から選択される、
    請求項１０に記載の環状ウレア誘導体またはその薬学的に許容される塩。     R 1 is represented by -CH 2 NR 3 R 4 or -CH 2 OR 5 .
    R 3 and R 4 are independently hydrogen atom, C 1-6 alkyl group (may be further substituted with hydroxy group), C 2-6 alkynyl group, C 2-6 alkenyl group, C 3 Represents a -6 cycloalkyl group, a C 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 together with the nitrogen atom to which they are attached. May contain 1 to 2 oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms, and may have substituents, 4 to 10 member monocyclic or two. A cyclic saturated cyclic amino group may be formed,
    R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
    The cyclic urea derivative according to claim 10 or a pharmaceutically acceptable salt thereof.
  12. 　Ｒ1が置換基を有してもよいフェニル基または置換基を有してもよいピリジル基であり、当該置換基が、ハロゲン原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基である、請求項１０に記載の環状ウレア誘導体またはその薬学的に許容される塩； R 1 is a phenyl group which may have a substituent or a pyridyl group which may have a substituent, and the substituent is a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and a hydroxymethyl group. The cyclic urea derivative according to claim 10, which is 1 to 3 substituents selected from the group consisting of, or a pharmaceutically acceptable salt thereof;
  13. 　Ｒ1が
    １）水素原子、
    ２）シアノ基で置換されていてもよいＣ１－６アルキル基、
    ３）-ＣＨ２ＮＲ３Ｒ４または-ＣＨ２ＯＲ５で表され、
    　Ｒ３、Ｒ４は、それぞれ独立して、水素原子、Ｃ１－６アルキル基（ヒドロキシ基でさらに置換されていてもよい）、Ｃ２－６アルケニル基、Ｃ３－６シクロアルキル基、Ｃ１－６アシル基（ヒドロキシ基でさらに置換されていてもよい）、メタンスルホニル基またはシアノメチル基を表し、あるいは、Ｒ３とＲ４はそれらが結合する窒素原子と一緒になり、１～２個の酸素原子、硫黄原子（スルホキシド、スルホンを含む）、ケイ素原子またはリン原子を含んでもよい、置換基を有することのある、５員から１０員の単環性もしくは二環性の飽和環状アミノ基を形成してもよく、該飽和環状アミノ基は、ハロゲン原子、オキソ基、メトキシ基、ヒドロキシ基、ヒドロキシメチル基、カルボキシ基、メトキシカルボニル基、ジメチルカルバモイル基、メチルカルバモイル基、およびジフルオロメチル基よりなる群から選択される１または２個の置換基で置換されていてもよく、
    　Ｒ５は、水素原子、Ｃ１－４アルキル基およびベンジル基から選択され、
    ４）臭素原子、塩素原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基で置換されていてもよいフェニル基、または
    ５）ハロゲン原子、ビニル基、メトキシ基、シアノ基、ヒドロキシ基およびヒドロキシメチル基よりなる群から選択される１～３個の置換基で置換されていてもよいピリジル基、
    である、請求項１に記載の環状ウレア誘導体またはその薬学的に許容される塩。     R 1 is 1) hydrogen atom,
    2) C 1-6 alkyl group, which may be substituted with a cyano group,
    3) Represented by -CH 2 NR 3 R 4 or -CH 2 OR 5
    Independently, R 3 and R 4 are a hydrogen atom, a C 1-6 alkyl group (which may be further substituted with a hydroxy group), a C 2-6 alkenyl group, a C 3-6 cycloalkyl group, and a C. Representing a 1-6 acyl group (which may be further substituted with a hydroxy group), a methanesulfonyl group or a cyanomethyl group, or R 3 and R 4 are combined with the nitrogen atom to which they are attached, 1-2. 5- to 10-membered monocyclic or bicyclic saturated cyclic amino groups, which may contain substituents, may contain oxygen atoms, sulfur atoms (including sulfoxides, sulfones), silicon atoms or phosphorus atoms. The saturated cyclic amino group may be composed of a halogen atom, an oxo group, a methoxy group, a hydroxy group, a hydroxymethyl group, a carboxy group, a methoxycarbonyl group, a dimethylcarbamoyl group, a methylcarbamoyl group, and a difluoromethyl group. May be substituted with one or two substituents selected from the group of
    R 5 is selected from a hydrogen atom, a C 1-4 alkyl group and a benzyl group.
    4) A phenyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a bromine atom, a chlorine atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and a hydroxymethyl group, or 5). A pyridyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group and a hydroxymethyl group.
    The cyclic urea derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
  14. 　実施例１～２３０に記載された環状ウレア誘導体またはその薬学的に許容される塩。 The cyclic urea derivative described in Examples 1-230 or a pharmaceutically acceptable salt thereof.
  15. 請求項１から１４のいずれか一項に記載の環状ウレア誘導体またはその薬学的に許容される塩を有効成分として含有する医薬。 A pharmaceutical agent containing the cyclic urea derivative according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.
  16. 請求項１から１４のいずれか一項に記載の環状ウレア誘導体またはその薬学的に許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition containing the cyclic urea derivative according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.
  17. 請求項１から１４のいずれか一項に記載の環状ウレア誘導体またはその薬学的に許容される塩を有効成分として含有する、ＤＹＲＫが関与する疾患の治療剤及び／又は予防剤。 A therapeutic agent and / or a preventive agent for a disease associated with DYRK, which comprises the cyclic urea derivative according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.
  18. ＤＹＲＫが関与する疾患が、前頭側頭型認知症、進行性核上性麻痺、大脳皮質基底核変性症、レビー小体型認知症、血管性認知症、外傷性脳損傷、慢性外傷性脳症、脳卒中、アルツハイマー病、パーキンソン病、ダウン症、鬱病ならびにこれらに伴う精神遅滞、記憶障害、記憶喪失、学習障害、知的障害、認知機能障害、軽度認知障害、認知症症状あるいは脳腫瘍、膵臓がん、卵巣がん、骨肉腫、大腸がん、肺がん、骨吸収疾患、骨粗鬆症、鎌状赤血球貧血、慢性腎疾患または骨吸収疾患である、請求項１７に記載の治療剤及び／又は予防剤。 Diseases involving DYRK include frontal temporal dementia, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, Levy body dementia, vascular dementia, traumatic brain injury, chronic traumatic encephalopathy, and stroke. , Alzheimer's disease, Parkinson's disease, Down's disease, depression and associated mental retardation, memory disorder, memory loss, learning disorder, intellectual disability, cognitive dysfunction, mild cognitive disorder, dementia symptoms or brain tumor, pancreatic cancer, ovary The therapeutic and / or prophylactic agent according to claim 17, which is osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis, sickle red erythrocyte anemia, chronic renal disease or bone resorption disease.
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