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  • 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
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  • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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  • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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  • A61P35/00—Antineoplastic agents
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  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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  • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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  • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

• the present invention relates to pharmaceuticals, especially novel alkyne derivatives having a DYRK inhibitory effect or pharmaceutically acceptable salts thereof.
• DYRK Dual-specificity tYrosine-phosphorylation Regulated protein kinase
• DYRK 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 in humans are DYRK1A, DYRK1B, DYRK2, DYRK3 and DYRK4 (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 mitochondrial dysfunction is considered as one of the causes (Non-Patent Document 4). It is known that an enzyme called parkin, which is involved in proteolysis, has 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 documents). 5).
• the DYRK1A gene is located in the Down's syndrome critical region, and it has been reported that mice overexpressing DYRK1A have abnormal 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 development 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).
• DYRK1A compounds that inhibit DYRK1A are considered to be useful in the treatment of neuropsychiatric disorders such as Alzheimer's disease, Down's syndrome, mental retardation, memory impairment, amnesia 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 epidermal growth factor receptor (EGFR) (Non-Patent Document 9). Therefore, a compound that inhibits DYRK1A is considered to be useful for treating EGFR-dependent cancer by suppressing the growth of cancer cells in 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, compounds that inhibit DYRK1B are considered to be useful in the treatment of pancreatic cancer, ovarian cancer, osteosarcoma, colon cancer and lung cancer (Non-Patent Documents 11, 12, 13, 14, 15).
• 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 alkyne 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.
• R 1 is a hydrogen atom, a halogen atom, a trimethylsilyl group, an aryl group which may be substituted, a heteroaryl group which may be substituted, a lower alkyl group which may be substituted, or an substituted alkyl group.
• R 2 and R 3 are independently hydrogen atom, halogen atom, optionally substituted lower alkyl group, optionally substituted cycloalkyl group, optionally substituted aryl group, and optionally substituted.
• Q indicates a structure selected from the following structures (a) to (o).
• R 4 is a hydrogen atom, a lower alkyl group which may be substituted, a cycloalkyl group which may be substituted, an alkylcarbonyl group which may be substituted, an alkylsulfonyl group which may be substituted, and an substituted alkylsulfonyl group. Represents a good saturated heterocyclic group, R 5 represents a hydrogen atom or a lower alkyl group which may be substituted. ) An alkyne derivative represented by or a pharmaceutically acceptable salt thereof.
• the present invention comprises administering to a patient in need of treatment a therapeutically effective amount of the alkyne derivative according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof.
• a method for treating and / or preventing a disease involving DYRK. (15) The alkyne derivative according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof for producing a therapeutic agent and / or a preventive agent for a disease involving DYRK. use.
• the drug described in (10) above is classified into an anticancer drug, an antipsychotic drug, an anti-dementia drug, an antiepileptic drug, an anti-seven drug, a gastrointestinal drug, a thyroid hormone drug or an antithyroid drug.
• 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 as 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 for tumors such as brain tumors It is useful as a therapeutic drug (pharmaceutical composition).
• 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 as 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 for 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 and chronic renal disease bone resorption disease and osteoporosis. Further, as a compound that inhibits DYRK, it is useful as a reagent for pathological imaging related to the above-mentioned diseases and a reagent for basic experiments and research.
• the novel alkyne derivative of the present invention has the following formula (I):
• R 1 is a hydrogen atom, a halogen atom, a trimethylsilyl group, an aryl group which may be substituted, a heteroaryl group which may be substituted, a lower alkyl group which may be substituted, or an substituted alkyl group.
• R 2 and R 3 are independently hydrogen atom, halogen atom, optionally substituted lower alkyl group, optionally substituted cycloalkyl group, optionally substituted aryl group, and optionally substituted.
• Q indicates a structure selected from the following structures (a) to (o).
• R 4 is a hydrogen atom, a lower alkyl group which may be substituted, a cycloalkyl group which may be substituted, an alkylcarbonyl group which may be substituted, an alkylsulfonyl group which may be substituted, and an substituted alkylsulfonyl group. Represents a good saturated heterocyclic group, R 5 represents a hydrogen atom or a lower alkyl group which may be substituted. ) It is a compound indicated by.
• DYRK represents Dual-speciality tyrosine-phosphoylation Regenerated protein Kinase, and is one of the DYRK families (DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4 or more).
• the “lower alkyl group” means a linear or branched saturated hydrocarbon group (C 1-6 alkyl group) having 1 to 6 carbon atoms.
• C 1-6 alkyl group a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
• the lower alkyl group preferably, "C 1-4 alkyl group” is mentioned, and more preferably, "C 1-3 alkyl group” is mentioned.
• Specific examples of the “lower alkyl group” include, for example, a methyl group, an ethyl group, an n-propyl group, a 1-methylethyl group, an n-butyl group, a tert-butyl group, a 1-methylpropyl group and a 2-methylpropyl group.
• cycloalkyl group means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure.
• cycloalkyl group preferably, "C 3-7 cycloalkyl group” is mentioned, and more preferably, "C 3-6 cycloalkyl group” is mentioned.
• cycloalkyl group examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, an adamantyl group and the like.
• the "aryl group” means an aromatic cyclic group having 6 to 14 carbon atoms.
• aryl group preferably, “C 6-10 aryl group” is mentioned, and more preferably, “C 6 aryl group” is mentioned.
• aryl group examples include, for example, a phenyl group and a naphthyl group.
• Heteroaryl group means a 5- to 10-membered heterocyclic aromatic cyclic group containing at least one heteroatom selected from the group of nitrogen, sulfur and oxygen atoms.
• the “heteroaryl group” is preferably a 5- to 8-membered heteroaryl group, more preferably a 5- or 6-membered heteroaryl group.
• heteroaryl group examples include an imidazolyl group, a pyrazolyl group, a thiazolyl group, a thienyl group, a frill group, a pyrrole group, a pyridyl group and the like.
• “Saturated heterocyclic group” means a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic group containing at least one heteroatom selected from the group of nitrogen, sulfur and oxygen atoms. do.
• saturated heterocyclic group include preferably a 3- to 6-membered saturated heterocyclic group, and more preferably a 5- or 6-membered heterocyclo group.
• saturated heterocyclic group examples include an epoxy group, an oxetanyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group and the like. ..
• a "heterocyclic fused cyclic group” is a bicyclic cyclic group in which a 3- to 8-membered ring is condensed, and comprises at least one heteroatom selected from the group of nitrogen atom, sulfur atom and oxygen atom.
• heterocyclic fused ring group preferably includes a heterocyclic fused ring group having a 3- to 6-membered alicyclic or aromatic ring-type heterocyclic group, and more preferably a 5- or 6-membered fat. Examples thereof include heterocyclic fused ring groups having a heterocyclic or aromatic ring-type heterocyclic group.
• heterocyclic condensed ring group examples include a tetrahydroisoquinolyl group, a benzothiophenyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, an indolyl group, an isoquinolyl group, a phthalimide group and the like.
• the "alkoxy group” means an oxy group substituted with the "lower alkyl group” or a 3- to 6-membered cyclic alkyl group.
• alkoxy group preferably, "C 1-6 alkoxy group” is mentioned, and more preferably, "C 1-3 alkoxy group” is mentioned.
• alkoxy group examples include, for example, a methoxy group, an ethoxy group, a propoxy group, a 1-methylethoxy group, a butoxy group, a 1,1-dimethylethoxy group, a 1-methylpropoxy group, a 2-methylpropoxy group, and the like.
• alkynyl group means a linear or branched saturated hydrocarbon group (C 2-6 alkynyl group) having 1 to 3 triple bonds and 2 to 6 carbon atoms.
• alkynyl group preferably, “C 2-5 alkynyl group” is mentioned, and more preferably, “C 2-4 alkynyl group” is mentioned.
• Specific examples of the “alkynyl group” include an ethynyl group, a propargyl group, a 2-butynyl group and the like.
• alkenyl group means a linear or branched saturated hydrocarbon group (C 2-6 alkenyl group) having 1 to 3 double bonds and 2 to 6 carbon atoms.
• alkenyl group preferably, "C 2-5 alkenyl group” is mentioned, and more preferably, “C 2-4 alkenyl group” is mentioned.
• Specific examples of the “alkenyl group” include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 2-methylallyl group and the like.
• alkylcarbonyl group means the above-mentioned “lower alkyl group” or a carbonyl group substituted with a 3- to 6-membered cyclic alkyl group, and examples thereof include an acetyl group.
• alkylsulfonyl group means a sulfonyl group substituted with the "lower alkyl group” or a 3- to 6-membered cyclic alkyl group, and examples thereof include a methylsulfonyl group.
• examples of the sulfonamide group which may be substituted include a methyl sulfonamide group and an ethyl sulfonamide group.
• the amino group which may be substituted may be, for example, any of an amino group having a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, and specifically, an amino group or a methylamino. Groups, dimethylamino groups and the like can be mentioned.
• Examples of the carbamoyl group which may be substituted include a methylcarbamoyl group, an ethylcarbamoyl group, a dimethylcarbamoyl group and the like.
• the thioether group which may be substituted may be, for example, any thioether group having a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, and specifically, a methylsulfanyl group or an ethyl. Examples thereof include a sulfanyl group, an isopropylsulfanyl group, a cyclopropylsulfanyl group and the like.
• Examples of the alkoxycarbonyl group include a methoxycarbonyl group and an ethoxycarbonyl group.
• the "substituent" of a good alkylsulfonyl group, optionally substituted sulfonamide group can be any chemically capable position of one or more of any kind of substituents.
• each substituent may be the same or different.
• substituents include a C 3-6 cycloalkyl group, a halogen atom, a C 1-4 alkoxy group, a cyano group, a benzyloxy group, a phenyl group, a hydroxy group, a methanesulfonyl group, and a substituted or unsubstituted amino group. Illustrated. Unless otherwise specified, the "substituted group" of an aryl group which may be substituted, a heteroaryl group which may be substituted, or a heterocyclic fused ring which may be substituted may be one or more.
• any type of substituent may be present at any chemically possible position, and when there are two or more substituents, the respective substituents may be the same or different.
• Specific examples of the substituent include a halogen atom, a vinyl group, a methoxy group, a cyano group, a hydroxy group, a hydroxymethyl group and the like.
• the halogen atom corresponds to a chlorine atom (Cl), a bromine atom (Br), a fluorine atom (F) and an iodine atom (I), and Cl, Br and F are particularly preferable.
• the definitions and preferable ranges of R 1 , R 2 , R 3 , R 4 , R 5 , and Q are as follows, but the technical aspects of the present invention are as follows. The range is not limited to the range of compounds listed below.
• R 1 is preferably a hydrogen atom, a lower alkyl group which may be substituted or a cycloalkyl group which may be substituted, and more preferably a lower alkyl group which may be substituted.
• R 2 it is also lower alkyl groups are a hydrogen atom or a substituent, more preferably a hydrogen atom.
• R 3 is preferably a optionally substituted lower alkyl group or a hydrogen atom, and more preferably a optionally substituted lower alkyl group.
• the R 4 is optionally substituted lower alkyl group.
• the R 5 is hydrogen atom.
• the Q is preferably (a), (b), (c), (d), (f), (g), (i), (j) (m), (n) or (o). More preferably, it is (a), (b), (d), (g), (m), or (n) or (o).
• preferred compounds include the following alkyne derivatives or pharmaceutically acceptable salts thereof.
• R 1 is a hydrogen atom or "C 1-4 alkyl group”
• R 2 is a hydrogen atom or "C 1-4 alkyl group”
• R 3 is a hydrogen atom or "C 1-4 alkyl group”.
• a compound in which Q is (a), (b), (d), (m), (n) or (o).
• More preferred compounds include the following alkyne derivatives or pharmaceutically acceptable salts thereof.
• R 1 is a "C 1-3 alkyl group”
• R 2 is a hydrogen atom or a "C 1-3 alkyl group”
• R 3 is a hydrogen atom.
• Even more preferable compounds include the following compounds or pharmaceutically acceptable salts thereof.
• R 1 is a "C 1-3 alkyl group”
• R 2 is a "C 1-3 alkyl group”
• R 3 is a hydrogen atom, and so on.
• a compound in which Q is (a), (b) or (m).
• preferred compounds include the following alkyne derivatives or pharmaceutically acceptable salts thereof.
• Examples of the pharmaceutically acceptable salt 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. 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., and 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 depending on, for example, the type of substituent.
• the chemical structure of only one form of those isomers may be described, but in the present invention, all isomers (geometric isomers, stereoisomers, tautomers) that may occur structurally are described. Etc.) are also included, including isomers alone or all mixtures thereof.
• the "hydrogen atom" include 1 H and 2 H (D), any one or more of the 1 H and 2 H (D of the compound represented by the formula (I) ) Is also included in the compound represented by the formula (I).
• 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, Protecting 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 is obtained by reacting the compound (II) with a condensing agent such as 1,1'-carbonyldiimidazole (CDI) or di (N-succinimidyl) (DSC) in a solvent.
• a condensing agent such as 1,1'-carbonyldiimidazole (CDI) or di (N-succinimidyl) (DSC)
• An excess amount of the condensing agent can be used, but it can be synthesized preferably by reacting with 1 to 5 molar equivalents of CDI or DSC.
• the solvent may be any solvent as long as it is inert to the reaction, and is not particularly limited, but for example, THF, DMF, DMA and the like can be used, and DMF can be preferably 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 at room temperature for
• Compound (II) used as a raw material for Scheme 1 can be produced, for example, by the method shown in Scheme 2.
• R 1 , R 2 , R 3 and Q are synonymous with the description in (I) above, L represents a lower alkyl group, and PG represents a protecting group.
• Compound (II) can be produced by reacting compound (III) with amine (IV) in a solvent such as THF, acetonitrile or DMA or in the absence of a solvent to deprotect. That is, the compound (II) can be reacted with the compound (III) in an amount of 3 to 10 molar equivalents of the amine (IV) to synthesize the compound (II) in which the amino group is protected.
• the reaction can be carried out in the range of room temperature to 150 ° C. for several minutes to several days, but can be synthesized by reacting at 80 ° C. to 120 ° C. for several hours to 24 hours.
• Compound (II) can be obtained by deprotecting an amino protecting group under conditions commonly used in organic chemistry.
• the compound (II-b) having the structure of Q (b) can also be produced, for example, by the method shown in Scheme 3.
• R 1 , R 2 and R 3 are synonymous with the description in (I) above, and PG represents a protecting group.
• the compound (II-b) is deprotected after converting aniline (V) to thioisocyanate (VI) and then reacting with amine (IV) to synthesize thiourea (VII) with a brominating agent.
• thioisocyanate (VI) can be obtained by reacting aniline (V) with 1 to 10 molar equivalents of thiophosgene in an aqueous solution, with the reaction ranging from -30 ° C to room temperature for a few minutes to 24 minutes. It can be carried out in hours, but it can be synthesized by reacting at ⁇ 10 ° C. to 0 ° C. for 1 to 4 hours.
• Thiourea (VII) is obtained by reacting the obtained thioisocyanate (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. Can be obtained.
• 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 10 ° C. to room temperature for several hours to 24 hours.
• the resulting thiourea (VII) is reacted with a large excess of acetic acid and 0.9-1 molar equivalents of bromine in a solvent such as acetonitrile or DCM to give the amino group protected compound (II-b).
• the amino group-protected compound (II-b) was also synthesized by reacting with a brominating agent such as 5 to 10 molar equivalents of sodium hydrogen carbonate and 0.9 to 1 molar equivalent of benzyltrimethylammonium tribromid. can do.
• 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 10 ° C.
• the compound (II-c) having the structure of Q (c) can also be produced, for example, by the method shown in Scheme 4.
• R 1 , R 2 and R 3 are synonymous with the description in (I) above, and PG represents a protecting group.
• Compound (II-c) is prepared by reacting thiocarbonylimidazole (IX), which can be prepared from amine (VIII) and 1,1'-dithiocarbonyldiimidazole, with amine (IV) to obtain thiourea (X) in a solvent. It can be produced by reacting with a brominating agent to form a thiazole ring and then deprotecting it. That is, thiocarbonylimidazole (IX) can be obtained by reacting amine (VIII) with 1 to 10 molar equivalents of 1,1'-dithiocarbonyldiimidazole in a solvent such as THF or DCM. The reaction can be carried out in the range of ⁇ 30 ° C. to 60 ° C. for several minutes to 24 hours, but can be synthesized by reacting at 10 ° C. to room temperature for 1 hour to 24 hours.
• Thiourea (X) can be obtained by reacting the obtained thiocarbonylimidazole (IX) with 1 to 1.5 molar equivalents of amine (IV) in a solvent such as THF.
• the reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to 24 hours, but is preferably synthesized by reacting at 10 ° C. to room temperature for 30 minutes to 2 hours.
• the resulting thiourea (X) can be reacted with a large excess of acetic acid and 0.9-1 molar equivalents of bromine in a solvent such as acetonitrile to give the amino group protected compound (II-c).
• the reaction can be carried out in the range of 0 ° C. to room temperature for several minutes to 18 hours, but is preferably synthesized by reacting at 10 ° C. to room temperature for 30 minutes to 2 hours.
• the amino group-protected compound (II-c) was also synthesized by reacting with a brominated reagent such as 5 to 10 molar equivalents of sodium hydrogen carbonate and 0.9 to 1 molar equivalent of benzyltrimethylammonium tribromid. can do.
• 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 10 ° C. to room temperature for several hours to 24 hours.
• Compound (II-c) can be obtained by deprotecting the protecting group of an amino group under conditions commonly used in organic chemistry.
• amine (VIII) with another corresponding aniline derivative in Scheme 4, the compound of formula (I) having Q having a structure of (a), (b), (d) to (o) is similarly processed. Can be manufactured.
• the compound (II-d) having the structure of Q (d) can also be produced, for example, by the method shown in Scheme 5.
• R 1 , R 2 and R 3 are synonymous with the description in (I) above, and PG represents a protecting group.
• Compound (II-d) is prepared by reacting thiourea (XII) obtained by reacting amine (XI) with 1,1'-dithiocarbonyldiimidazole and amine (IV) with a brominating agent in a solvent to form a thiazole ring. It can be manufactured by deprotecting after forming. That is, thiourea is reacted by simultaneously adding 1 to 5 molar equivalents of 1,1'-dithiocarbonyldiimidazole and 1 to 5 molar equivalents of amine (XI) to amine (IV) in a solvent such as THF. (XII) can be obtained. The reaction can be carried out in the range of ⁇ 30 ° C. to 60 ° C. for several minutes to 24 hours, but can be synthesized by reacting at 10 ° C. to room temperature for 30 minutes to 4 hours.
• the resulting thiourea (XII) is reacted with a large excess of acetic acid and 0.9-1 molar equivalents of bromine in a solvent such as acetonitrile or DCM to give the amino group protected compound (II-d).
• a compound (II-d) having an amino group protected can also be obtained by reacting with a brominating agent such as 5 to 10 molar equivalents of sodium hydrogen carbonate and 0.9 to 1 molar equivalent of benzyltrimethylammonium tribromid. be able to.
• the reaction can be carried out in the range of ⁇ 30 ° C. to room temperature for several minutes to 18 hours, but is preferably synthesized by reacting at ⁇ 10 ° C. to 0 ° C. for 30 minutes to 2 hours.
• Compound (II-d) can be obtained by deprotecting an amino protecting group under conditions commonly used in organic chemistry.
• the amine (IV) used as a raw material for Schemes 2 to 5 can be produced, for example, by the method shown in Scheme 6.
• R 1 , R 2 and R 3 are synonymous with the description in (I) above, and PG represents a protecting group.
• Amine (IV) can be produced by converting the hydroxyl group of compound (XIII) into a phthaloyl group using the Mitsunobu reaction and deprotecting the phthalimide. That is, amine (IV) is produced by reacting compound (XIII) with 1 to 5 molar equivalents of diethyl azodicarboxylate and 1 to 5 molar equivalents of triphenylphosphine and 1 to 5 molar equivalents of phthalimide in a solvent such as THF. A phthaloyl protector can be obtained. The reaction can be carried out in the range of ⁇ 30 ° C. to room temperature for several minutes to 24 hours, but is preferably synthesized by reacting at ⁇ 10 ° C. to 0 ° C.
• Amine (IV) can be obtained by reacting the obtained phthaloyl-protected product of amine (IV) with a large excess of hydrazine hydrate in a solvent such as ethanol.
• the reaction can be carried out in the range of room temperature to 100 ° C. for several minutes to 24 hours, but is preferably synthesized by reacting at 40 ° C. to 70 ° C. for 2 hours to 24 hours.
• the compound (XIII) used as a raw material for Scheme 6 can be produced, for example, by the method shown in Scheme 7.
• R 1 , R 2 and R 3 are synonymous with the description in (I) above, M represents a metal such as lithium or magnesium, and PG represents a protecting group.
• Compound (XIII) can be produced by the Grignard reaction of aldehyde (XIV) and alkyne (XV). That is, compound (XIII) can be obtained by reacting aldehyde (XIV) with a Grignard reagent prepared from 5 to 10 molar equivalents of alkyne (XV) in a solvent such as THF. The reaction can be carried out in the range of ⁇ 80 ° C. to room temperature for several minutes to 24 hours, but is preferably synthesized by reacting at ⁇ 80 ° C. to ⁇ 20 ° C. for 30 minutes to 2 hours.
• the aldehyde (XIV) used as a raw material for Scheme 7 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 (XIII) used as a raw material for Scheme 6 can also be produced, for example, by the method shown in Scheme 8.
• R 1 , R 2 and R 3 are synonymous with the description in (I) above, M represents a metal such as lithium or magnesium, and PG represents a protecting group.
• Compound (XIII) can be produced by reducing the ketone (XVII) obtained by the reaction of Weinrebamide (XVI) with the Grignard reagent of alkyne (XV). That is, a ketone (XVII) can be obtained by reacting Weinrebamide (XVI) with a Grignard reagent prepared from 5 to 10 molar equivalents of alkyne (XV) in a solvent such as THF. The reaction can be carried out in the range of ⁇ 80 ° C. to room temperature for several minutes to 24 hours, but is preferably synthesized by reacting at ⁇ 80 ° C. to ⁇ 20 ° C. for 1 hour to 4 hours.
• ketone (XVII) is reacted with a reducing agent such as 1 to 5 molar equivalents of sodium borohydride and a borane complex in a solvent such as methanol or THF in the presence or absence of a catalyst to form a compound (XIII).
• a reducing agent such as 1 to 5 molar equivalents of sodium borohydride and a borane complex in a solvent such as methanol or THF
• a catalyst such as methanol or THF
• the compound (III-a) having the structure of Q (a) can be produced, for example, by the method shown in Scheme 9.
• L represents a lower alkyl group and X represents a halogen.
• mercaptobenzothiazole (XIX) obtained by cyclizing bromoaniline (XVIII) with potassium ethylxanthogenate is alkylated with an alkyl halide, and the obtained alkylthioether is oxidized with an oxidizing agent.
• mercaptobenzothiazole (XIX) can be obtained by subjecting bromoaniline (XVIII) 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.
• a corresponding alkyl thioether can be obtained by reacting the obtained mercaptobenzothiazole (XIX) with 3 to 4 molar equivalents of an alkyl halide in a solvent such as DMF in the presence of a base such as potassium carbonate.
• 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 10 ° C. to room temperature for 30 minutes to 4 hours.
• the obtained alkylthioether can be used in a solvent such as acetic acid, water or DCM in a solvent such as 0.8 to 2.5 molar equivalents of metachloroperbenzoic acid (m-CPBA), a peroxide such as hydrogen peroxide, or KMnO 4 (.
• Compound (III-a) can be obtained by oxidizing with an oxidizing agent used in ordinary organic synthesis such as potassium permanganate). The reaction can be carried out in the range of 0 ° C. to room temperature for 10 minutes to 2 days, but is preferably synthesized by reacting at 10 ° C. to room temperature for 10 minutes to 2 hours.
• bromoaniline (XVIII) with another corresponding bromoaniline derivative, the compound of formula (I) having a structure of Q (b) to (o) can be produced in the same manner. ..
• the compound of the present invention represented by the formula (I) can also be produced, for example, by the method shown in Scheme 10.
• R 1 , R 2 , R 3 and Q are synonymous with the description in (I) above, L represents a lower alkyl group, and PG represents a protecting group.
• the compound (I) of the present invention has an amide group by reacting the compound (XX) with the compound (III) in a solvent such as THF, acetonitrile and DMA in the presence of a base such as potassium carbonate, cesium carbonate and sodium hydride. Can synthesize the protected compound (I).
• the reaction can be carried out in the range of 0 ° C. to 150 ° C. for several minutes to several days, but can be synthesized by reacting at room temperature to 100 ° C. for several hours to 24 hours.
• Compound (I) can be obtained by deprotecting the protecting group of the obtained compound (I) in which the amide group is protected under the conditions generally used in organic chemistry.
• the compound (XX) used as a raw material of Scheme 10 can be produced, for example, by the method shown in Scheme 11.
• R 1 , R 2 , R 3 and Q are synonymous with the description in (I) above, and PG represents a protecting group.
• Compound (XX) contains compound (IV) in a solvent in the presence of a base such as TEA, an imidazole-based condensing agent such as 1,1'-carbonyldiimidazole (CDI), di (N-succinimidyl) (DSC), or the like. It can be obtained by reacting with a carbonic acid ester-based condensing agent or the like. An excess amount of the condensing agent can be used, but it can be synthesized preferably by reacting with 1 to 3 molar equivalents of CDI or DSC.
• a base such as TEA
• an imidazole-based condensing agent such as 1,1'-carbonyldiimidazole (CDI), di (N-succinimidyl) (DSC), or the like. It can be obtained by reacting with a carbonic acid ester-based condensing agent or the like. An excess amount of the condensing agent can be used, but it can be
• the solvent may be any solvent as long as it is inert to the reaction, and is not particularly limited, but for example, THF, DCM, DMA and the like can be used, and DCM can be preferably 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 at room temperature for about 30 minutes to 5 hours.
• 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 starch such as lactose, 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 can be prepared by dissolving or suspending the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof in an aqueous solution containing sucrose, carboxymethyl cellulose and the like.
• 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 dose of the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be changed according to the type, severity, age, sex, body weight, dosage form and the like of the disease. However, it is usually in the range of 1 mg to 1,000 mg per day in adults, which can be administered in one, two or three divided doses by the oral or parenteral route.
• the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof should be used as a DYRK inhibitor as a reagent for pathological imaging related to the above-mentioned diseases, a reagent for basic experiments, and a reagent for research. Can be done.
• 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.
• To the ethyl acetate solution (6.0 mL) of this intermediate was added a 4M hydrochloric acid-ethyl acetate solution (10 mL, 40 mmol) under 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 on ice, 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).
• This intermediate was dissolved in a mixed solvent of THF-methanol 1: 1 (24 mL), then hydrazine monohydrate (4.8 g, 95 mmol) was added, and the mixture was stirred at 50 ° C. for 3 hours.
• the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.
• the residue was diluted with ethyl acetate, washed with 1 M aqueous sodium hydroxide solution, and then extracted with 1 M hydrochloric acid.
• the obtained acidic extract was made alkaline with a 2M aqueous sodium hydroxide solution and extracted with ethyl acetate.
• the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, a 4M hydrochloric acid-dioxane solution (3 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes. An aqueous sodium hydroxide solution was added to the reaction mixture 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.
• Example 2 (R) -1-([1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-yl) -5- (1-propyne-1-yl)
• RS -1-([1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-yl) -5- (propynyl) produced in Example 1
• Imidazolidine-2-one (0.15 g, 0.49 mmol) was purified using supercritical fluid chromatography (Chiralpak IG (30 x 250 mm), carbon dioxide / methanol) as the previously eluted fraction.
• Example 3 (S) -1-([1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-yl) -5- (1-propyne-1-yl)
• RS imidazolidine-2-one
• Example 1 Imidazolidine-2-one (0.15 g, 0.49 mmol) was purified using supercritical fluid chromatography (Chiralpak IG (30 ⁇ 250 mm), carbon dioxide / methanol) and carried out. The fraction eluted after the R form of Example 2 (retention time 2.37 minutes) (retention time 4.19 minutes) was obtained as the title compound having the reverse configuration (yield 40 mg).
• 1 H NMR 500MHz, DMSO-d 6 ) ⁇ (ppm) 8.04 (br.
• Example 5 (4S, 5R) -1- (7,8-dihydrobenzoflo [4,5-d] thiazole-2-yl) -4-methyl-5- (propa-1-in-1-yl) imidazolidine- 2-on manufacturing
• the diastereomeric mixture obtained in the eighth step of Example 4 was purified by supercritical fluid chromatography (Chiralpak IC (30 ⁇ 250 mm), carbon dioxide / methanol) and (4S, 5S) -1-.
• the compounds [Table 1] to [Table 3] of Examples 8 to 22, 24 to 54, and 56 to 84 below are derived from the corresponding raw materials (commercially available products or commercially available compounds by a method known from the commercially available compounds or a method similar thereto). Derivatized compound) was used, and if necessary, it was produced by appropriately combining the methods usually used in synthetic organic chemistry according to the method described in the above-mentioned Examples.
• the compound having an asymmetric center was produced by chiral starting material, asymmetric synthesis, preparative purification by a chiral column, or a combination thereof.
• the physicochemical data of each compound are shown in [Table 4] and [Table 5].
• Example 23 (4S, 5R) -1-([1,3] dioxolo [4', 5': 5,6] benzo [1,2-d] thiazole-7-yl) -4-methyl-5- (proper) 1-In-1-yl) Production of imidazolidine-2-one (First step) DCM solution (30 mL) of tert-butyl ((2S, 3RS) -3-aminohex-4-in-2-yl) carbamate (1.0 g, 4.72 mmol) obtained in the fourth step of Example 4. TEA (1.32 mL, 9.43 mmol) and N, N'-discusin imidazole carbonate (1.32 g, 5.17 mmol) were added to the mixture.
• Test Example 1 [Activity inhibition test for DYRK family (DYRK1A, DYRK1B, DYRK2, DYRK3)] (Measurement method of kinase activity) Kinase activity was measured by the Mobility Shift Assay (MSA) method using QuickScout Screening Assay TM MSA (commercially available kit from Carna Biosciences). As the substrate for the kinase reaction, the FITC-labeled DYRKtide peptide included in the kit was used.
• Substrate (4 ⁇ M), MgCl 2 (20 mM) and ATP (DYRK1A; 100 ⁇ M, DYRK1B; 200 ⁇ M, DYRK2) using assay buffer [20 mM HEPES, 0.01% Triton X-100 TM, 2 mM dithiothreitol, pH 7.5].
• a substrate mixture of 40 ⁇ M, DYRK3; 20 ⁇ M) was prepared.
• kinases (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.
• A, B, and C represent P / (P + S) in the blank well, P / (P + S) in the control solution well, and P / (P + S) in the compound addition well, respectively.
• IC 50 values were calculated by regression analysis of the percentage inhibition and a test compound concentration (log).
• Tables 7 and 8 show the inhibitory activity of the representative compound of the present invention on DYRK1A, DYRK1B, DYRK2, and DYRK3.
• Kinase activity inhibition the IC 50 value *** mark less than 0.01 [mu] M, 0.1 [mu] M under the mark ** least 0.01 [mu] M, less than or 0.1 [mu] M 1 [mu] M * mark, the more 1 [mu] M - indicated by the symbol (ND has not been measured).
• 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 loss, amnesia, depression. It is useful as a preventive or therapeutic agent for psychiatric / 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 for 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 and chronic renal disease bone resorption disease and osteoporosis.
• a compound that inhibits DYRK it is useful as a reagent for pathological imaging related to the above-mentioned diseases and a reagent for basic experiments and research.

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