WO2022059779A1 - アミン誘導体 - Google Patents
アミン誘導体 Download PDFInfo
- Publication number
- WO2022059779A1 WO2022059779A1 PCT/JP2021/034327 JP2021034327W WO2022059779A1 WO 2022059779 A1 WO2022059779 A1 WO 2022059779A1 JP 2021034327 W JP2021034327 W JP 2021034327W WO 2022059779 A1 WO2022059779 A1 WO 2022059779A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- benzothiazole
- imidazole
- dihydroflo
- compound
- substituted
- Prior art date
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- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- QLBHNVFOQLIYTH-UHFFFAOYSA-L dipotassium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O QLBHNVFOQLIYTH-UHFFFAOYSA-L 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 239000008131 herbal destillate Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000013016 learning Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004065 mitochondrial dysfunction Effects 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- WBGPDYJIPNTOIB-UHFFFAOYSA-N n,n-dibenzylethanamine Chemical compound C=1C=CC=CC=1CN(CC)CC1=CC=CC=C1 WBGPDYJIPNTOIB-UHFFFAOYSA-N 0.000 description 1
- FLSFXZBPPCIMLC-UHFFFAOYSA-N n,n-diethylethanamine;1h-pyridin-2-one Chemical compound CCN(CC)CC.O=C1C=CC=CN1 FLSFXZBPPCIMLC-UHFFFAOYSA-N 0.000 description 1
- BKEHNGMBGCQOPQ-UHFFFAOYSA-N n,n-diethylethanamine;pyridine-3-carboxylic acid Chemical compound CC[NH+](CC)CC.[O-]C(=O)C1=CC=CN=C1 BKEHNGMBGCQOPQ-UHFFFAOYSA-N 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- WTQUVYBGJUBJSW-UHFFFAOYSA-N oxacycloundecane Chemical group C1CCCCCOCCCC1 WTQUVYBGJUBJSW-UHFFFAOYSA-N 0.000 description 1
- ZEERHWXRRLRIQO-UHFFFAOYSA-N oxan-4-yl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1CCOCC1 ZEERHWXRRLRIQO-UHFFFAOYSA-N 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 108700007244 parkin Proteins 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- IQKKBPJEPPCXTA-UHFFFAOYSA-N potassium acetonitrile cyanide Chemical compound [C-]#N.[K+].C(C)#N IQKKBPJEPPCXTA-UHFFFAOYSA-N 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000001995 reticulocyte Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011986 second-generation catalyst Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000003797 telogen phase Effects 0.000 description 1
- AAIOQVDUALRIDJ-VIFPVBQESA-N tert-butyl (2S)-2-methyl-3,6-dihydro-2H-pyridine-1-carboxylate Chemical compound C[C@H]1CC=CCN1C(=O)OC(C)(C)C AAIOQVDUALRIDJ-VIFPVBQESA-N 0.000 description 1
- COWVSHYGRCIMEK-QMMMGPOBSA-N tert-butyl (2s)-2-methyl-4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C[C@H]1CC(OS(=O)(=O)C(F)(F)F)=CCN1C(=O)OC(C)(C)C COWVSHYGRCIMEK-QMMMGPOBSA-N 0.000 description 1
- HQMYWQCBINPHBB-QMMMGPOBSA-N tert-butyl (2s)-2-methyl-4-oxopiperidine-1-carboxylate Chemical compound C[C@H]1CC(=O)CCN1C(=O)OC(C)(C)C HQMYWQCBINPHBB-QMMMGPOBSA-N 0.000 description 1
- UJLDFDMDAGJZSV-SFYZADRCSA-N tert-butyl (3s,4r)-3,4-diaminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](N)C1 UJLDFDMDAGJZSV-SFYZADRCSA-N 0.000 description 1
- KTTVLVUNLLVBMY-UHFFFAOYSA-N tert-butyl 4-azaspiro[2.5]oct-7-ene-4-carboxylate Chemical compound CC(C)(C)OC(N1C2(CC2)C=CCC1)=O KTTVLVUNLLVBMY-UHFFFAOYSA-N 0.000 description 1
- BUXIMDQFTMQURO-UHFFFAOYSA-N tert-butyl spiro[7-oxa-3-azabicyclo[4.1.0]heptane-2,1'-cyclopropane]-3-carboxylate Chemical compound CC(C)(C)OC(N1C2(CC2)C2OC2CC1)=O BUXIMDQFTMQURO-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 150000003527 tetrahydropyrans Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical group C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 108091005990 tyrosine-phosphorylated proteins Proteins 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—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
- 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
- C07D513/04—Ortho-condensed systems
-
- 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
- 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
- A61K31/4353—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Definitions
- the present invention relates to pharmaceuticals, in particular novel amine derivatives having DYRK inhibitory activity or pharmaceutically acceptable salts thereof.
- DYRK (Dual-specialty 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, ⁇ -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).
- 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 It has been reported that the DYRK1A gene is located in the Down's syndrome critical region, and that mice overexpressing DYRK1A have abnormal neuropsychiatric function and show 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).
- the compound that inhibits DYRK1A is considered to be useful for the treatment of neuropsychiatric disorders such as Alzheimer's disease, Down's disease, mental retardation, memory impairment, memory loss and Parkinson's disease.
- Non-Patent Document 9 the compound that inhibits DYRK1A suppresses the growth of cancer cells in EGFR-dependent brain tumors and tumors, and is useful for the treatment of EGFR-dependent tumors.
- DYRK1B is highly expressed in 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 (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).
- 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).
- Patent Document 2 is reported as an inhibitor of DYRK1A and DYRK1B.
- the amine derivative of the present invention is not described.
- the present invention is as follows.
- a 2 represents CR B , CR C R D , oxygen atom or NR A 1 .
- RA1, RA2 , RB, RC and RD each independently represent a hydrogen atom or a optionally substituted C 1-6 alkyl.
- R 1 represents a hydrogen atom, a halogen atom or a optionally substituted C 1-6 alkyl.
- X represents a carbon atom or a nitrogen atom and represents L 2 represents C 1-4 alkylene which may be substituted.
- RE represents a C 1-6 alkyl which may be substituted.
- Z represents -NR 2 R 3 or -OR 7 and represents R 7 represents an optionally substituted C 1-6 alkyl, or an optionally substituted C 1-7 alkylene formed with R 4 , where R 4 and R 7 are respectively. Together with the carbon and oxygen atoms to be bonded, they form a optionally substituted 5-11-membered saturated heterocycle.
- R 2 is a hydrogen atom, optionally substituted C 1-6 alkyl, C (O) -RE, C 3-10 cycloalkyl, C 2-6 alkynyl or 4-11 member saturated heterocycle ring.
- R 3 represents a hydrogen atom, optionally substituted C 1-6 alkyl or C (O) -RE.
- R4 represents a C 1-6 alkyl which may be substituted.
- R 2 and R 3 may be combined with the nitrogen atom to which they are bonded to form a optionally substituted 4-11-membered saturated heterocycle, or R 3 and R. 4 may, together with the nitrogen and carbon atoms to which it binds, form a optionally substituted 4-11-membered saturated heterocycle, or the above-mentioned R2 , R3 and nitrogen.
- Any carbon atom on a saturated heterocycle composed of atoms and R4 may be combined to form a 4-11 member saturated heterocycle.
- compound (1) or “compound represented by formula (1)”
- a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt thereof.
- Z represents -NR 2 R 3 and R 2 and R 3 each independently represent a hydrogen atom, optionally substituted C 1-6 alkyl or C (O) -RE, where , R 2 and R 3 together with the nitrogen atom to which they are bonded may form a optionally substituted 4-8 member saturated heterocycle, item 1 or a compound thereof.
- a pharmaceutically acceptable salt
- [Item 3] Z represents ⁇ NR 2 R 3 , and R 3 and R 4 together with the nitrogen and carbon atoms to which they are attached form a optionally substituted 4-8 member saturated heterocycle. , Item 1 or a pharmaceutically acceptable salt thereof.
- Item 5 The compound according to any one of Items 1-3, wherein R 1 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
- Item 5 The compound according to any one of Items 1-4 or a pharmaceutically acceptable salt thereof, wherein X is a carbon atom.
- Item 5 The compound according to Item 5, or a pharmaceutically acceptable salt thereof, wherein A 1 is an oxygen atom, A 2 is methylene, and L 1 is methylene.
- Equation (1) is the following equation (1a): [During the ceremony, A 2 represents a methylene or oxygen atom that may be substituted. L 1 represents methylene which may be substituted or ethylene which may be substituted. L 2 represents C 1-4 alkylene which may be substituted. R 2 and R 3 each independently represent a hydrogen atom, optionally substituted C 1-6 alkyl or C (O) -RE, where R 2 and R 3 are bonded together. Together with the nitrogen atom, it may form a optionally substituted 4-8 member saturated heterocycle. RE represents a C 1-6 alkyl which may be substituted. R4 is a C 1-6 alkyl which may be substituted. ], The compound according to Item 1, 2, 4, 5 or 6, or a pharmaceutically acceptable salt thereof.
- Item 6 The compound according to Item 7, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are C 1-6 alkyls which may be independently substituted.
- Item 7 The compound of Item 7 or pharmaceutically acceptable thereof, wherein R 2 and R 3 together with the nitrogen atom to which they are attached form a optionally substituted 4-8 member saturated heterocycle. Salt.
- Item 6 The compound according to any one of Items 7-9, wherein L 2 is C 1-3 alkylene, or a pharmaceutically acceptable salt thereof.
- Equation (1) is the following equation (1b): [During the ceremony, A 2 represents a methylene or oxygen atom that may be substituted. L 1 represents methylene which may be substituted or ethylene which may be substituted. l and m independently represent 1, 2 or 3, respectively, where the sum of l and m is 5 or less. n represents 1, 2, 3 or 4 R 2 represents a hydrogen atom, optionally substituted C 1-6 alkyl, C 3-10 cycloalkyl or C (O) -RE. RE represents a C 1-6 alkyl which may be substituted. RF represents a hydrogen atom, a halogen atom or an optionally substituted C 1-6 alkyl.
- the RFs may be the same or different, and two RFs on the same carbon atom are saturated with 4-8 members together with the carbon atom to which they are bonded.
- a spiro ring consisting of a heterocyclic ring or a 3-8-membered saturated carbon ring may be formed, or two RFs on different carbon atoms may be bonded to form a bridge.
- Item 5 The compound according to Item 11 or a pharmaceutically acceptable salt thereof, wherein R2 is a hydrogen atom, optionally substituted C 1-6 alkyl or C 3-10 cycloalkyl.
- Item 5 The compound according to Item 11 or a pharmaceutically acceptable salt thereof, wherein R2 is a C 1-6 alkyl which may be substituted.
- Item 5 The compound according to any one of Items 11-13 or a pharmaceutically acceptable salt thereof, wherein l and m are 1 or 2, respectively.
- Equation (1) is the following equation (1c): [During the ceremony, A 2 represents a methylene or oxygen atom that may be substituted. L 1 represents methylene which may be substituted or ethylene which may be substituted. p and q independently represent 1, 2 or 3, where the sum of p and q is 5 or less. t represents 1, 2, 3 or 4 RG represents a hydrogen atom, a halogen atom, a optionally substituted C 1-6 alkyl, an optionally substituted C 1-6 alkoxy or a CN group. When t is 2, 3 or 4, the RGs may be the same or different, and two RGs on the same carbon atom are saturated with 4-8 members together with the carbon atom to which they are bonded.
- a spiro ring consisting of a heterocyclic ring or a 3-8-membered saturated carbon ring may be formed, or two RGs on different carbon atoms may be bonded to form a bridge.
- Item 17 The compound according to any one of Items 1-16 or a pharmaceutically acceptable salt thereof selected from the group of the following compounds: cis-3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5-methyloctahydro-2H-imidazole [4,5-c] pyridin-2- On (Example 7); cis-3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5- (2-methoxyethyl) octahydro-2H-imidazole [4,5-c] Pyridine-2-one (Example 8); cis-1- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5-methyloctahydro-2H-imidazole [4,5-c] pyridin-2- On (Example 9); cis-3- (7,8
- a therapeutic agent and / or a preventive agent for a disease associated with DYRK which comprises the compound according to any one of Items 1-17 or a pharmaceutically acceptable salt thereof as an active ingredient.
- Diseases associated with DYRK include frontal temporal dementia, progressive supranuclear palsy, cerebral cortical basal nucleus degeneration, Lewy 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 impairment, memory loss, learning impairment, intellectual impairment, cognitive impairment, mild cognitive impairment, dementia symptoms or brain tumor, pancreatic cancer, ovary Item 20.
- the therapeutic agent and / or preventive agent according to Item 20 which is osteosarcoma, colon cancer, lung cancer, bone resorption disease, osteoporosis, sickle red erythrocyte anemia, chronic renal disease or bone resorption disease.
- Item 5 The compound according to any one of Items 1-17, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of diseases associated with DYRK.
- Item 28 Item 28, and at least selected from the drugs classified into anticancer drug, antipsychotic drug, nootropic drug, antiepileptic drug, antidepressant drug, gastrointestinal drug, thyroid hormone drug or antithyroid drug.
- [Item 26] In combination with at least one drug selected from drugs classified as anticancer drugs, antipsychotic drugs, dementia drugs, antiepileptic drugs, antidepressants, gastrointestinal drugs, thyroid hormone drugs or antithyroid drugs.
- 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 syndrome, depression and related complications, mental retardation, memory disorder, memory loss, learning disorder, intellectual disorder, cognitive dysfunction, mild cognitive disorder, treatment of dementia symptom progression or prevention of dementia onset or brain tumor, Item 8.
- 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.
- DYRK represents Dual-specificity tYrosine-phosphorylated protein kinase, and means one of the DYRK family (DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4 or more).
- halogen atom includes, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. It is preferably a fluorine atom.
- C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1-6 carbon atoms
- C 6 alkyl means a direct chain having 6 carbon atoms. It means a chain or branched saturated hydrocarbon group. The same applies to other numbers.
- C 1-6 alkyl preferably “C 1-4 alkyl” is mentioned, and more preferably “C 1-3 alkyl” is mentioned.
- Specific examples of “C 1-3 alkyl” include, for example, methyl, ethyl, propyl, 1-methylethyl and the like.
- C 1-4 alkyl include, for example, butyl, 1,1-dimethylethyl, 1-methylpropyl, and 2-methyl, in addition to those mentioned as specific examples of "C 1-3 alkyl".
- Examples include propyl.
- Specific examples of "C 1-6 alkyl” include, for example, pentyl 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1 in addition to those mentioned as specific examples of "C 1-4 alkyl”.
- -Methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like can be mentioned.
- C 1-6 Alkoxy means “C 1-6 Alkoxy”, and the "C 1-6 Alkoxy” moiety is synonymous with the “C 1-6 Alkoxy”.
- C 1-6 alkoxy preferably “C 1-4 alkoxy” is mentioned, and more preferably “C 1-3 alkoxy” is mentioned.
- Specific examples of “C 1-3 alkoxy” include methoxy, ethoxy, propoxy, 1-methylethoxy and the like.
- Specific examples of “C 1-4 alkoxy” include, for example, butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, and 2-methyl, in addition to those mentioned as specific examples of "C 1-3 alkoxy”. Alkoxy and the like can be mentioned.
- C 1-6 alkoxy include, for example, pentyroxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1 in addition to those mentioned as specific examples of "C 1-4 alkoxy”.
- -Methylbutoxy, 2-methylbutoxy, 4-methylpentyroxy, 3-methylpentyroxy, 2-methylpentyroxy, 1-methylpentyroxy, hexyloxy and the like can be mentioned.
- the "C 1-6 alkoxycarbonyl” is a "carbonyl” substituted with the "C 1-6 alkoxy”.
- the "C 1-6 alkoxycarbonyl” is preferably “C 1-4 alkoxycarbonyl” and more preferably “C 1-3 alkoxycarbonyl”.
- Specific examples of “C 1-3 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-methylethoxycarbonyl and the like.
- Specific examples of “C 1-4 alkoxycarbonyl” include, for example, butoxycarbonyl, 1,1-dimethylethoxycarbonyl, and 1-methylpropoxy, in addition to those listed as specific examples of "C 1-3 alkoxycarbonyl”.
- Examples thereof include carbonyl and 2-methylpropoxycarbonyl.
- C 1-6 alkoxycarbonyl include, for example, pentyroxycarbonyl, 1,1-dimethylpropoxycarbonyl, 1,2, in addition to those listed as specific examples of "C 1-4 alkoxycarbonyl”.
- C 1-7 alkylene is a linear or branched chain having 1-7, 1-4, 1-3 carbon atoms, respectively. It means a divalent saturated hydrocarbon group in the form.
- the "C 1-7 alkylene” is preferably “C 1-4 alkylene”
- the "C 1-4 alkylene” is preferably “C 1-3 alkylene”
- the "C 1-3 alkylene” is Preferred is “C 1-2 alkylene”.
- Specific examples of “C 1-2 alkylene” include methylene, ethylene and the like.
- Specific examples of “C 1-3 alkylene” include, for example, propylene, 1-methylethylene and the like in addition to those mentioned as specific examples of "C 1-2 alkylene”.
- C 1-4 alkylene include, for example, butylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1 in addition to those mentioned as specific examples of "C 1-3 alkylene”.
- C 1-3 alkylene -Methylpropylene, 2-methylpropylene and the like can be mentioned.
- C 1-7 alkylene include, for example, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1 in addition to those mentioned as specific examples of "C 1-4 alkylene”.
- C 2-6 alkynyl means a linear or branched saturated hydrocarbon group having 1 to 3 triple bonds and 2 to 6 carbon atoms.
- alkynyl preferably “C 2-4 alkynyl” is mentioned, and more preferably “C 2-3 alkynyl” is mentioned.
- alkynyl include ethynyl, propargyl, 2-butynyl and the like.
- the “C 3-10 cycloalkyl” means a cyclic saturated hydrocarbon group having 3-10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure.
- the "C 3-10 cycloalkyl” is preferably "C 3-7 cycloalkyl". Specific examples of "C 3-7 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- C 3-10 cycloalkyl include, for example, cyclooctyl, cyclononyl, cyclodecyl, adamantyl and the like in addition to those mentioned as specific examples of "C 3-7 cycloalkyl".
- “4-11-membered saturated heterocycle” means a monocyclic or bicyclic saturated heterocycle containing one or more heteroatoms selected from the group of nitrogen, oxygen and sulfur atoms, in part. Those having an unsaturated bond and those having a crosslinked structure are also included.
- a 7-membered saturated heterocycle ”.
- the "4-8 member saturated heterocycle” include, for example, azetidine ring, pyrrolidine ring, piperidine ring, azepan ring, azocane ring, morpholine ring, piperazine ring, oxazocane ring, azabicycloheptane ring, and azabicyclooctane ring. , Oxetane ring, thietan ring, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrane ring, thiomorpholine ring, 1,4-dioxane ring and the like.
- the "4-11-membered saturated heterocycle” include, for example, an azonan ring, an oxazonane ring, an azecan ring, and an oxazecan ring in addition to those mentioned as specific examples of the "4-8 member saturated heterocycle". , Azacycloundecane ring, Azabicyclononane ring, Azabicyclodecane ring and the like.
- the "3-8 member saturated carbocycle” means a monocyclic or bicyclic saturated aliphatic carbocycle, and includes those having a partially unsaturated bond and those having a crosslinked structure.
- the "3-8-membered saturated carbocycle” is preferably a "4-8-membered saturated carbocycle", more preferably a "5-8-membered saturated carbocycle", and even more preferably "5-8-membered saturated carbocycle”.
- a 7-member saturated carbocyclic ring ".
- 3-8 member saturated heterocycle examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, bicycloheptane and the like.
- the tricyclic heterocycle formed including A 1 , A 2 and L 1 represents a chemically stable heterocycle and has a partially unsaturated bond. Things are also included.
- the tricyclic heterocycle preferably has the structure shown below.
- the "4-8 member saturated heterocycle” include, for example, an azetidine ring, a pyrrolidine ring, a piperidine ring, an azepane ring, an azocane ring, a morpholine ring, a piperazine ring, an oxazocane ring, an azabicycloheptane ring, and an azabicyclooctane ring. And so on.
- the "4-11-membered saturated heterocycle” include, for example, an azonan ring, an oxazonane ring, an azecan ring, and an oxazecan ring in addition to those mentioned as specific examples of the "4-8 member saturated heterocycle". , Azacycloundecane ring, Azabicyclononane ring, Azabicyclodecane ring and the like.
- Z is ⁇ OR 7
- “a 5-11-membered saturated heterocycle formed by R4 and R7 together with a carbon atom and an oxygen atom to which they are bonded” is a cyclic structure thereof.
- atom means a monocyclic or bicyclic saturated heteroatom containing one or more heteroatoms other than the oxygen atom, and includes those having a partially unsaturated bond and those having a crosslinked structure.
- the "5-11 member saturated heterocycle formed by R4 and R7 together with the carbon atom and oxygen atom to which they are bonded preferably "5-8 member saturated heterocycle” is preferable.
- the "5-8 member saturated heterocycle” include a tetrahydrofuran ring, a tetrahydropyran ring, an oxepane ring, an oxocan ring and the like.
- the "5-11 member saturated heterocycle” include, for example, an oxonan ring, an oxecan ring, an oxacycloundecane ring, and the like, in addition to those mentioned as specific examples of the "5-8 member saturated heterocycle". Can be mentioned.
- a 2 is CR B , CR C R D , oxygen atom or NR A 1 , preferably CR C R D or oxygen atom, more preferably methylene or oxygen atom.
- L 2 is a optionally substituted C 1-4 alkylene, preferably methylene, ethylene or propylene. More preferably, it is methylene or ethylene.
- RA1, RA2 , RB, RC and RD are hydrogen atoms or optionally substituted C 1-6 alkyl, preferably hydrogen atoms.
- RE and RG are C 1-6 alkyl optionally substituted, preferably methyl.
- RF is a hydrogen atom, a halogen atom or a optionally substituted C 1-6 alkyl, preferably a hydrogen atom or an optionally substituted C 1-6 alkyl.
- R 1 is a hydrogen atom, a halogen atom or a optionally substituted C 1-6 alkyl, preferably a hydrogen atom or a halogen atom, and more preferably a hydrogen atom.
- R 2 is a hydrogen atom, optionally substituted C 1-6 alkyl, C (O) -RE, C 3-10 cycloalkyl, C 2-6 alkynyl or 4-11 member saturated heterocyclic ring. It is a group, preferably a hydrogen atom, optionally substituted C 1-6 alkyl or C 3-10 cycloalkyl, more preferably a hydrogen atom or optionally substituted C 1-6 alkyl. be.
- R 3 is a hydrogen atom, optionally substituted C 1-6 alkyl or C (O) -RE, preferably a hydrogen atom or optionally substituted C 1-6 alkyl.
- R4 is a optionally substituted C 1-6 alkyl, preferably a optionally substituted C 1-4 alkyl, more preferably methyl or ethyl.
- X is a carbon atom or a nitrogen atom, preferably a carbon atom.
- L, m, p and q are 1, 2 or 3, preferably 1 or 2.
- N and t are 1, 2, 3 or 4, preferably 1 or 2.
- Z is -NR 2 R 3 or -OR 7 , and when Z is -NR 2 R 3 , preferably R 2 and R 3 are substituted together with the nitrogen atom to which they are attached. It may form a 4-8-membered saturated heterocycle, or R 3 and R 4 may be substituted 4-8, together with the nitrogen and carbon atoms to which they are attached, respectively.
- R 7 may be substituted C 1-6 alkyl, or optionally substituted C 1- formed with R 4 . 7 alkylene, preferably substituted or optionally substituted methylene or optionally substituted ethylene, in which R 4 and R 7 are substituted together with the carbon and oxygen atoms to which they are attached, respectively. It forms a 5-8 member saturated heterocycle which may be.
- the substituents when "optionally substituted C 1-6 alkyl" is substituted include a halogen atom, hydroxy (the hydroxy may be substituted with a protective group of hydroxy), and the like.
- the saturated heterocycle may be substituted with a protective group of C 1-6 alkyl, halogen atom and nitrogen atom which may be substituted. Yes, it will be replaced at any replaceable position.
- the number of the substituents is preferably 1-5, more preferably 1-3. When substituted with two or more substituents, each substituent may be the same or different.
- substituents when "optionally substituted C 3-10 cycloalkyl" is substituted include halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 3- . It is one or more substituents selected from the group consisting of 10 cycloalkyl groups, and is substituted at any substitutable position. The number of the substituents is preferably 1-5, more preferably 1-3. When substituted with two or more substituents, each substituent may be the same or different.
- substituents when "optionally substituted C 1-6 alkoxy" is substituted include halogen atom, hydroxy, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 .
- the number of the substituents is preferably 1-5, more preferably 1-3.
- each substituent may be the same or different.
- substituent may be a halogen atom, hydroxy, halogen atom or C 1-6 alkyl substituted with hydroxy (the hydroxy may be substituted with a protective group of hydroxy), C 1-6 alkoxy. , C 3-8 cycloalkyl group, nitrile, C 1-6 alkoxycarbonyl, formyl, C 2-6 alkynyl group, oxo group and 4-11 member saturated heterocycle (even if the saturated heterocycle is substituted).
- each substituent may be the same or different, and the two substituents on the same carbon atom, together with the carbon atom to which they are bonded, are 4-8 members. It may form a spiro ring composed of a saturated heterocycle of 3-8 members or a saturated carbon ring of 3-8 members.
- the substituent when "optionally substituted ethylene" is substituted is C 1-6 alkyl which may be substituted with a halogen atom or hydroxy (the hydroxy is a protective group of hydroxy). Substituted), nitrile, C 1-6 alkoxycarbonyl, formyl, C 2-6 alkynyl group and 4-11 member saturated heterocycle (the saturated heterocycle may be substituted C 1- ). It is one or more substituents selected from the group consisting of 6 alkyl, halogen atom and nitrogen atom protective groups) and oxo groups, and is substituted at any substitutable position. The number of the substituents is preferably 1-4.
- each substituent When substituted with two or more substituents, each substituent may be the same or different, and the two substituents on the same carbon atom, together with the carbon atom to which they are bonded, are 4-8 members. It may form a spiro ring composed of a saturated heterocycle of 3-8 members or a saturated carbon ring of 3-8 members.
- the substituent is a halogen atom or hydroxy.
- C 1-6 alkyl optionally substituted the hydroxy may be substituted with a protective group of hydroxy
- nitrile C 1-6 alkoxycarbonyl, formyl, C 2-6 alkynyl group, oxo group and 4
- One or more selected from -11-membered saturated heterocycles the saturated heterocycles may be substituted with optionally substituted C 1-6 alkyl, halogen atom and nitrogen atom protective groups). It is a substituent and is substituted at any substitutable position.
- the number of the substituents is preferably 1-4.
- each substituent may be the same or different, and the two substituents on the same carbon atom, together with the carbon atom to which they are bonded, are 4-8 members. It may form a spiro ring composed of a saturated heterocycle of 3-8 members or a saturated carbon ring of 3-8 members.
- “saturated heterocycle of” and the “optionally substituted 5-11-membered saturated heterocycle” may have may be substituted with a halogen atom, hydroxy, halogen atom or hydroxy.
- C 1-6 alkyl (the hydroxy may be substituted with a hydroxy protective group), C 1-6 alkoxy, C 3-8 cycloalkyl, nitrile, C 1-6 alkoxycarbonyl, formyl, C 2-6 .
- Alkinyl group, oxo group and 4-11 member saturated heterocycle (the saturated heterocycle may be substituted with a C 1-6 alkyl substituted group and a protective group of a halogen atom and a nitrogen atom). It is one or more substituents selected from the group consisting of, and is substituted at any substitutable position. The number of the substituents is preferably 1-5, more preferably 1-3. When substituted with two or more substituents, each substituent may be the same or different, and the two substituents on the same cyclic carbon atom, together with the carbon atom to which they are bonded, 4-. It may form a spiro ring consisting of an 8-membered saturated heterocycle or a 3-8-membered saturated carbon ring, or two substituents on different cyclic carbon atoms are bonded to form a bridge. You may.
- preferred compounds include the following compounds or pharmaceutically acceptable salts thereof.
- a 1 is an oxygen atom
- a 2 is methylene
- L 1 is methylene
- L 2 is optionally substituted C 1-4 alkylene
- X is a carbon atom
- R 1 is hydrogen.
- a 1 is an oxygen atom
- a 2 is methylene
- L 1 is methylene
- L 2 is methylene or ethylene
- X is a carbon atom
- R 1 is a hydrogen atom
- a 1 is an oxygen atom
- a 2 is methylene
- L 1 is methylene
- L 2 is optionally substituted C 1-4 alkylene
- X is a carbon atom
- R 1 is hydrogen.
- a 1 is an oxygen atom
- a 2 is methylene
- L 1 is methylene
- L 2 is methylene or ethylene
- X is a carbon atom
- R 1 is a hydrogen atom
- R4 is methyl or ethyl.
- a 1 may be an oxygen atom
- a 2 may be methylene
- L 1 may be methylene
- X may be a carbon atom
- R 1 may be a hydrogen atom
- R 2 may be a hydrogen atom or substituted.
- a 1 is an oxygen atom
- a 2 is methylene
- L 1 is methylene
- X is a carbon atom
- R 1 is a hydrogen atom
- R 2 may be substituted C 1-6 .
- a 1 and A 2 are oxygen atoms, L 1 is methylene or ethylene, X is a carbon atom, R 1 is a hydrogen atom, and L 2 is a optionally substituted C 1-4 alkylene.
- a 1 and A 2 are oxygen atoms, L 1 is methylene or ethylene, X is a carbon atom, L 2 is a optionally substituted C 1-4 alkylene, and R 1 is a hydrogen atom. Yes, R 2 and R 3 together with the bonding nitrogen atom form a optionally substituted 4-11-membered saturated heterocycle, and R 4 may be substituted C 1 .
- a 1 and A 2 may be oxygen atoms
- L 1 may be methylene or ethylene
- X may be a carbon atom
- R 1 may be a hydrogen atom
- R 2 may be a hydrogen atom or substituted C 1- .
- a 1 is an oxygen atom
- a 2 is methylene
- L 1 is methylene or ethylene
- L 2 is a optionally substituted C 1-4 alkylene
- X is a carbon atom and R 1 Is a hydrogen atom
- Z is ⁇ OR 7
- R 7 is a optionally substituted C 1-7 alkylene formed with R 4 , where R 4 and R 7 are bonded, respectively.
- a 1 is an oxygen atom
- a 2 is methylene
- L 1 is methylene or ethylene
- L 2 is methylene or ethylene
- X is a carbon atom
- R 1 is a hydrogen atom
- Z is.
- R 7 is a optionally substituted C 1-7 alkylene formed with R 4 , with R 4 and R 7 together with the carbon and oxygen atoms to which they are attached, respectively.
- a compound that forms a 5-11-membered saturated heterocycle which may be substituted.
- a 1 and A 2 are oxygen atoms
- L 1 is methylene or ethylene
- L 2 is optionally substituted C 1-4 alkylene
- X is a carbon atom
- R 1 is a hydrogen atom.
- Z is -OR 7
- R 7 is a optionally substituted C 1-7 alkylene formed with R 4
- R 4 and R 7 are carbon atoms and oxygen to which they are attached, respectively.
- a 1 and A 2 are oxygen atoms
- L 1 is methylene or ethylene
- L 2 is methylene or ethylene
- X is a carbon atom
- R 1 is a hydrogen atom
- Z is -OR 7 .
- R 7 is a optionally substituted C 1-7 alkylene formed with R 4 , where R 4 and R 7 are substituted together with the carbon and oxygen atoms to which they are attached, respectively.
- a compound that forms a 5-11-membered saturated heterocycle which may be.
- preferable compounds include the following compounds or pharmaceutically acceptable salts thereof.
- more preferable compounds include the following compounds or pharmaceutically acceptable salts thereof.
- the compound of the present invention is synthesized by a production method shown below and a method combining a known compound and a known synthesis method.
- the compounds in the reaction formula also include the case of forming a salt, and examples of the salt include the same as the salt of the compound (1). It should be noted that these reactions are merely examples, and the compound of the present invention can be appropriately produced by another method based on the knowledge of a person who is proficient in organic synthesis.
- the functional group is protected as necessary.
- the desired product may be obtained by deprotecting after completion of the reaction or after performing a series of reactions.
- protecting group examples include, for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Willy and Sons, Inc., 19 (19), etc.
- the usual protecting groups described in the above can be used, and more specifically, as the protecting group of the amino group, for example, tert-butoxycarbonyl, benzyloxycarbonyl, dimethylformamide, p-toluenesulfonyl, o- Nitrobenzenesulfonyl, tetrahydropyranyl, etc., as a protecting group for hydroxy groups, for example, trialkylsilyl, acetyl, benzyl, tetrahydropyranyl, methoxymethyl, etc., as protecting groups for aldehyde groups, for example, dialkylacetal, cyclic, etc.
- Examples of the protecting group for the carboxyl group include alkyl acetal and the like, for example, tert-butyl ester, ortho ester, acid amide and the like.
- the compound in which these functional groups are protected is also included in the compound of the above formula (1).
- protecting groups are commonly used in synthetic organic chemistry (eg, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and S. , Inc., New York (1999), etc.) or a method similar thereto.
- R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , L 1 , L 2 , R E , and X are synonymous with the description in Item 1 above;
- R 2a and R 3a are , Representing a optionally substituted C 1-6 alkyl;
- R 5 represents an optionally substituted C 1-5 alkyl;
- LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, -Represents an O-substituted sulfonyl group (eg, methanesulfonyl group, p-toluenesulfonyl group, etc.);
- PG represents a protecting group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, etc.).
- PG represents a protecting group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group
- Step 1-1 Manufacturing step of compound (1-3)
- Compound (1-3) is a method similar to a known synthesis method for compound (1-1) (eg, Chemical & Pharmaceutical Bulletin, 1406, (2007), Advanced Synthesis & Catalysis, 1643, (2005), etc.). It can be obtained by reacting with compound (1-2).
- Compound (1-1) was produced by a known synthetic method (for example, Bioorganic & Medicinal Chemistry Letters, 28, (2007), J. Org. Chem. 2613, (1986), etc.) or a synthetic method thereof. Can be used.
- the compound (1-2) As the compound (1-2), a commercially available product or a known synthetic method (for example, Tetrahedron Letters, 946, (2015), Synlett, 426, (1999), etc.) or a compound produced by a synthetic method thereof is used. be able to.
- Step 1-2 Manufacturing step of compound (1-4)
- Compound (1-4) is produced by cyclizing compound (1-3) by a method similar to a known synthetic method (for example, Journal of Organic Chemistry, 8693, (2003), WO2013043001 etc.).
- Step 1-3 Manufacturing step of compound (1-5) Compound (1-5) cyclizes compound (1-4) in a manner similar to known synthetic methods (eg, Organic Letters, 5136, (2015), Bioorganic & Medicinal Chemistry, 822, (2008), etc.). Manufactured by
- Step 1-4 Manufacturing step of compound (1-9)
- Compound (1-9) is obtained by reacting compound (1-5) with compound (1-6) in an inert solvent in the presence of a boron hydride compound and, if necessary, an acid. Can be done.
- a commercially available product or a compound produced by a known synthetic method for example, US200619965, Journal of Medicinal Chemistry, 3680, (2003), etc.
- a synthetic method thereof can be used as the compound (1-6).
- the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane; Protonic polar solvents such as methanol, ethanol, 1-propanol, 2-propanol, and water; and mixed solvents thereof and the like can be mentioned. Tetrahydrofuran, dichloromethane, chloroform and methanol are preferable.
- the acid examples include carboxylic acids such as formic acid, propionic acid, acetic acid and trifluoroacetic acid; and mineral acids such as hydrochloric acid.
- boron borohydride compound examples include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like. Preferred are sodium triacetoxyborohydride and sodium cyanoborohydride.
- the reaction temperature is not particularly limited, but is usually selected from the range from 0 ° C. to the boiling point of the solvent used.
- the temperature is preferably 0 ° C to 20 ° C.
- the reaction time is usually 30 minutes to 72 hours.
- Compound (1-9) is also produced by using compound (1-7) and a base and, if necessary, reacting with compound (1-5) in an inert solvent in the presence of a halogenating agent. ..
- a commercially available product or a compound produced by a known synthetic method for example, US2013 / 1503254, EP1679308, (2006), etc.
- a synthetic method based on the same can be used.
- the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene, xylene and pyridine; acetonitrile and propio.
- Aprotonic polar solvents such as nitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and Examples thereof include these mixed solvents.
- Acetonitrile, N, N-dimethylacetamide and dimethyl sulfoxide are preferable.
- the base include organic bases such as triethylamine, diisopropylethylamine and pyridine; and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide and sodium hydroxide. Preferred are diisopropylethylamine, potassium carbonate and cesium carbonate.
- halogenating agent examples include inorganic halides such as potassium iodide and sodium iodide; and organic halides such as tetrabutylammonium iodide.
- the reaction temperature is not particularly limited, but is usually selected from the range from 0 ° C. to the boiling point of the solvent used.
- the temperature is preferably 0 ° C to 100 ° C.
- the reaction time is usually 30 minutes to 72 hours.
- the compound (1-9) uses a carboxylic acid (1-8) and a condensing agent, or an acid anhydride corresponding to the carboxylic acid (1-8), and is inactive in the presence of a base and an additive, if necessary. It is also produced by reacting with compound (1-5) in a solvent.
- Carboxylic acid (1-8) or the corresponding acid anhydride may be a commercially available or known synthetic method (eg, Journal of Organic Chemistry 2564, (1999), Organic Letters 4739, (2004), etc.) or a synthetic method thereof. Those manufactured by the method can be used.
- the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene, xylene and pyridine; acetonitrile and propio.
- Aprotonic polar solvents such as nitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and Examples thereof include these mixed solvents.
- Preferred are N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, chloroform and dichloromethane.
- condensing agent examples include dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, and benzotriazole-1-yl-tris (dimethylamino) phosphonium / hexafluorophosphorus products.
- additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine.
- the reaction can be carried out.
- the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine.
- the reaction temperature is not particularly limited, but is usually selected from a range of about -20 ° C to the boiling point of the solvent used.
- the temperature is preferably 0 ° C to 20 ° C.
- the reaction time is usually 10 minutes to 48 hours.
- Step 2-1 Manufacturing step of compound (2-2)
- Compound (2-2) is produced by using compound (1-1) and compound (2-1) according to the method described in step 1-1.
- the compound (2-1) a compound produced by a known synthetic method (for example, Chemical Communications 7693, (2015), WO2015061572, etc.) or a synthetic method similar thereto can be used.
- Step 2-2 Manufacturing step of compound (2-3) Compound (2-3) is produced using compound (2-2) according to the method described in Step 1-2.
- Step 2-3 Manufacturing step of compound (2-4) Compound (2-4) is produced according to the method described in Step 1-3 after undergoing deprotection of the protecting group using compound (2-3).
- Step 2-4 Manufacturing step of compound (2-5)
- Compound (2-5) reacts compound (2-4) with a sulfonyl chloride in the presence of a base in an inert solvent after deprotecting the protecting group when LG is a substituted sulfonyl group.
- a base in an inert solvent after deprotecting the protecting group when LG is a substituted sulfonyl group.
- compound (2-4) can be obtained by reacting with a halogenating agent in an inert solvent after deprotecting the protecting group.
- the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; aromatic hydrocarbons such as toluene and xylene; chloroform, dichloromethane, 1, Halogenated hydrocarbons such as 2-dichloroethane; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone; and mixed solvents thereof and the like. .. Tetrahydrofuran, chloroform and dichloromethane are preferable.
- the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, 2,4,6-trimethylpyridine and 4-dimethylaminopyridine. Preferred are triethylamine and diisopropylamine.
- sulfonyl chloride examples include methanesulfonyl chloride, monochloromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, o-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride and the like. It is preferably methanesulfonyl chloride.
- halogenating agent examples include thionyl chloride, oxalyl dichloride, phosphorus tribromide and the like. Thionyl chloride and phosphorus tribromide are preferred.
- the reaction temperature is not particularly limited, but is usually selected from the range from -20 ° C to the boiling point of the solvent used.
- the temperature is preferably 0 ° C to 60 ° C.
- the reaction time is usually 5 minutes to 24 hours.
- Step 2-5 Production of Compound (2-7)
- Compound (2-7) is a compound (2-5) in which the compound (2-5) is mixed with a base in an inert solvent and optionally in the presence of a halide (2-7). It can be obtained by reacting with 6).
- a commercially available product or a compound produced by a known synthetic method for example, WO20073965, US2010216812, etc.
- a synthetic method similar thereto can be used as the compound (2-6.
- the inert solvent include ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane; halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane; Aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof and the like can be mentioned.
- ether solvents such as tetrahydrofuran, tetrahydropyran, 1,4-dioxane and 1,2-dimethoxyethane
- halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane
- Aprotonic polar solvents such as acetonitrile, N, N-dimethylformamide, N, N-
- the base examples include organic bases such as triethylamine, diisopropylethylamine, pyridine, 2,4,6-trimethylpyridine and 4-dimethylaminopyridine; and inorganic bases such as potassium carbonate, sodium carbonate and cesium carbonate.
- organic bases such as triethylamine, diisopropylethylamine, pyridine, 2,4,6-trimethylpyridine and 4-dimethylaminopyridine
- inorganic bases such as potassium carbonate, sodium carbonate and cesium carbonate.
- halide examples include organic halides such as tetrabutylammonium iodide and tetrabutylammonium bromide; and inorganic halides such as potassium iodide, potassium bromide, sodium iodide, and sodium bromide.
- the reaction temperature is not particularly limited, but is usually selected from the range from ⁇ 20 ° C. to the boiling point of the solvent or compound (2-6) used.
- the temperature is preferably 0 ° C to 120 ° C.
- the reaction time is usually 30 minutes to 72 hours.
- Manufacturing method 3 The compound represented by the formula (1-4) is also produced, for example, by the method shown below. [In the formula, R 1 , R 2 , R 3 , R 4 , A 1 , A 2 , L 1 , L 2 , X are synonymous with the description in Item 1 above; even if R 3a is substituted.
- LG represents a leaving group (eg, iodine atom, bromine atom, chlorine atom, —O-substituted sulfonyl group (eg, methanesulfonyl group, p-toluenesulfonyl group, etc.), etc.)
- PG represents a protecting group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group, benzyl group, etc.).
- Step 3-1 Manufacturing step of compound (3-2)
- Compound (3-2) is produced by using compound (1-1) and compound (3-1) according to the method described in step 1-1.
- the compound (3-1) a commercially available product or a compound produced by a known synthetic method (for example, WO2008136457, WO2014015905, etc.) or a synthetic method similar thereto can be used.
- Step 3-2 Manufacturing step of compound (3-3) Compound (3-3) is produced using compound (3-2) according to the method described in Step 1-2.
- Step 3-3 Manufacturing step of compound (3-4) Compound (3-4) is produced using compound (3-3) according to the method described in Step 2-4.
- Step 3-4 Manufacturing step of compound (3-5)
- Compound (3-5) is produced by using compound (3-4) and synthesizing it by a method similar to a known synthetic method (for example, Journal of Medicinal Chemistry 3918, (1995), WO2015177326, etc.).
- Step 3-5 Manufacturing step of compound (1-4)
- Compound (1-4) is also produced by using compound (3-5) and synthesizing it by a method similar to a known synthetic method (for example, Bioorganic & Medicinal Chemistry Letters 5227 (2007), WO2016044641 etc.). ..
- Manufacturing method 4 The compound represented by the formula (4-5) is produced, for example, by the method shown below.
- R 1 , A 1 , A 2 , L 1 , X are synonymous with the description of item 1 above, and RG , p, q, t are synonymous with the description of item 16 above;
- Y represents a halogen atom (eg, iodine atom, bromine atom, chlorine atom, etc.);
- PG represents a protecting group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group, etc.).
- Step 4-1 Manufacturing step of compound (4-3)
- Compound (4-3) is produced by using compound (4-1) and compound (4-2) according to the method described in step 1-1.
- the compound (4-1) is prepared by a known synthetic method (for example, Bioorganic & Medicinal Chemistry Letters, 28, (2007), Journal of Organic Chemistry 2613, (1986), etc.) or a synthetic method thereof. Can be used.
- Step 4-2 Manufacturing step of compound (4-4)
- Compound (4-4) is cyclized using compound (4-3) by a method similar to a known synthetic method (for example, Chemical Communications 446, (2004), Journal of Organic Chemistry 8719, (2009), etc.).
- Step 4-3 Manufacturing step of compound (4-5) Compound (4-5) is produced according to the method described in Step 1-3 after undergoing deprotection of the protecting group using compound (4-4).
- Step 5-1 Manufacturing step of compound (5-2)
- Compound (5-2) is produced using compound (1-1) and compound (5-1) according to the method described in step 1-1.
- Compound (5-1) is produced as a commercially available product or by a known synthetic method (for example, Journal of the American Chemical Society, 12521, (1996), Green Chemistry 451, (2005), etc.) or a synthetic method thereof. Can be used.
- Step 5-2 Manufacturing step of compound (5-3) Compound (5-3) is produced using compound (5-2) according to the method described in Step 1-2.
- Step 5-3 Manufacturing step of compound (5-4) Compound (5-4) is produced using compound (5-3) according to the method described in Step 1-3.
- the compound of the present invention having a desired functional group at a desired position can be obtained.
- Isolation and purification of intermediates and products in the above production method shall be carried out by appropriately combining methods used in ordinary organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, and various chromatographies. Can be done. Further, the intermediate can be subjected to the next reaction without any particular purification.
- Examples of the “pharmaceutically acceptable salt” include acid addition salts and base addition salts.
- an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, or citrate, oxalate, phthalate, etc.
- organic acid salts such as salts and camphor sulfonates.
- Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt and aluminum salt, or trimethylamine, triethylamine, pyridine, picolin, 2,6-lutidine, ethanolamine and diethanolamine. , Triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylamine, organic base salts and the like.
- examples of the "pharmaceutically acceptable salt” include amino acid salts with basic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid or acidic amino acids.
- Suitable salts of raw material compounds and intermediates and acceptable salts as raw materials for pharmaceuticals are conventional non-toxic salts, such as organic acid salts (eg, acetates, trifluoroacetates, maleates, fumals). Hydrolates, citrates, tartrates, methanesulfonates, benzenesulfonates, formates or p-toluenesulfonates, etc.) and inorganic acid salts (eg, hydrochlorides, hydrobromide, hydroiodide, etc.) Acid addition salts such as salts, sulfates, nitrates or phosphates), salts with amino acids (eg arginine, aspartic acid or glutamate etc.), alkali metal salts (eg sodium salt or potassium salt etc.) and alkaline earth Metal salts such as metal salts (eg calcium salt or magnesium salt), ammonium salts, or organic base salts (eg trimethylamine salt, triethylamine salt
- the raw material compound or intermediate in the above production method may exist in the form of a salt such as, for example, hydrochloride depending on the reaction conditions and the like, but can be used as it is or in a free form.
- a salt such as, for example, hydrochloride depending on the reaction conditions and the like
- these are dissolved or suspended in a suitable solvent, and a base such as an aqueous sodium hydrogen carbonate solution is used. It can be converted to a free form by neutralizing with etc.
- Some compounds (1) or pharmaceutically acceptable salts thereof may contain tautomers such as keto-enol, positional isomers, geometric isomers or optical isomers. However, all possible isomers, including these, and mixtures in any proportion of the isomers are also included in the invention.
- the optical isomer can be separated by carrying out a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the above-mentioned production method. Further, an optically active substance can also be used as a starting material.
- the compound in which the stereochemistry (S, R) is expressed in the chemical structural formula means an optically active substance, and when the stereochemistry is not particularly expressed, it means a racemic compound.
- a cis form and a trans form are present, and in particular, when the solid (S, R) is not indicated, it means a racemic form.
- the salt of compound (1) may be purified as it is if it can be obtained, and if compound (1) is obtained in a free form, compound (1) is suitable. It may be dissolved or suspended in a solvent, and an acid or a base may be added to form a salt. Further, compound (1) or a pharmaceutically acceptable salt thereof may exist in the form of a solvate with water or various solvents, and these solvates are also included in the present invention.
- the "hydrogen atom” includes 1 H and 2 H (D), and any one or more of the compounds represented by the formula ( 1 ) is converted into 2 H (D).
- the converted deuterium converter is also included in the compound represented by the formula (1).
- the compound of the present invention can be formulated and administered directly or by using an appropriate dosage form by oral administration or parenteral administration.
- the dosage form include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and paps.
- the pharmaceutical product is produced by a known method using a pharmaceutically acceptable additive.
- Additives include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , Perfume and the like can be used.
- lactose mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, stear.
- examples thereof include magnesium acid, stearyl sodium fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
- the administration route of the compound of the present invention may be oral administration, parenteral administration or rectal administration, and the daily dose thereof varies depending on the type of compound, administration method, patient's symptom / age and the like.
- oral administration usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per 1 kg body weight of a human or a mammal can be administered in one to several divided doses.
- parenteral administration such as intravenous injection, for example, about 0.01 to 300 mg, more preferably about 1 to 100 mg per 1 kg body weight of a human or a mammal can be administered.
- the compound (1) of the present invention or a pharmaceutically acceptable salt thereof can be used as a DYRK inhibitor as a reagent for pathological imagery related to the above-mentioned diseases, a reagent for basic experiments, and a reagent for research.
- Reference Example 1 and Reference Example 2 Reference Example 1: tert-butyl cis-3-amino-4- ⁇ [(2,3-dihydro-1-benzofuran-4-yl) carbamoti oil] amino ⁇ piperidine-1-carboxylate
- Reference Example 2 tert- Butyl cis-4-amino-3- ⁇ [(2,3-dihydro-1-benzofuran-4-yl) carbamoti oil] amino ⁇ piperidine-1-carboxylate Ice-cooled 4-isothiocianato-2,3-dihydrobenzofuran (886 mg) in a chloroform solution (20 mL) of cis-1-Boc-3,4-diaminopiperidine (1.08 g) and N, N-diisopropylethylamine (647 mg).
- Reference example 3-7 The compounds of Reference Examples 3 to 7 were obtained by using the corresponding raw material compounds according to the methods described in Reference Example 1 and Reference Example 2.
- Reference examples 9 to 13 The compounds of Reference Examples 9 to 13 were obtained by using the corresponding raw material compounds according to the method described in Reference Example 8.
- Reference example 15-19 The compounds of Reference Examples 15 to 19 were obtained by using the corresponding raw material compounds according to the method described in Reference Example 14.
- Reference example 21 The compound of Reference Example 21 was obtained by using the corresponding raw material compound according to the method described in Reference Example 20.
- Reference example 22 Benzyl Benzyl [(2R, 3S) -1- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ -3-hydroxybutane-2-yl] carbamate
- Sodium carbonate 5.57 g
- benzyl chloroformate (2.96 mL) were added to a mixed solution of the compound (5.42 g) of Reference Example 20 in tetrahydrofuran (45 mL) and water (30 mL), and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure.
- Reference example 23 The compound of Reference Example 23 was obtained by using the corresponding raw material compound according to the method described in Reference Example 22.
- Reference example 25 The compound of Reference Example 25 was obtained by using the corresponding raw material compound according to the method described in Reference Example 24.
- Reference example 27 The compound of Reference Example 27 was obtained by using the corresponding raw material compound according to the method described in Reference Example 26.
- Reference example 28 N-[(2S, 3S) -1- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ -3- (1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl) butane- 2-Indole] -N'-(2,3-dihydro-1-benzofuran-7-yl) thiourea
- Diisopropylethylamine (0.65 mL) and 4-isothiocianato-2,3-dihydrobenzofuran (226 mg) were added to a chloroform solution (5 mL) of the compound (444 mg) of Reference Example 27 under ice-cooling, and the mixture was stirred at room temperature for 3 hours.
- Reference example 29 The compound of Reference Example 29 was obtained by using the corresponding raw material compound according to the method described in Reference Example 28.
- Reference example 31 The compound of Reference Example 31 was obtained by using the corresponding raw material compound according to the method described in Reference Example 30.
- Reference example 33 The compound of Reference Example 33 was obtained by using the corresponding raw material compound according to the method described in Reference Example 32.
- Reference example 34 (4S, 5S) -5-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -1- (6,7-dihydroflo [2,3-e] [1,3] benzothiazole-2-yl ) -4-Methylimidazolidine-2-one
- Diisopropylethylamine (0.582 mL) and dicarbonate (N-succinimidyl) (307 mg) were added to a chloroform solution (10 mL) of the compound (490 mg) of Reference Example 32, and the mixture was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform.
- Reference example 35 The compound of Reference Example 35 was obtained by using the corresponding raw material compound according to the method described in Reference Example 34.
- Reference example 36 (4S, 5S) -1- (6,7-dihydroflo [2,3-e] [1,3] benzothiazole-2-yl) -5- (hydroxymethyl) -4-methylimidazolidine-2-one
- a 2M hydrogen chloride ethanol solution (1 mL) was added to a methanol suspension (5 mL) of the compound (295 mg) of Reference Example 34, and the mixture was stirred for 1 hour.
- a 2M hydrogen chloride ethanol solution (4 mL) was added, and the mixture was stirred for 5 hours. Further, a 2M hydrogen chloride ethanol solution (4 mL) was added, and the mixture was stirred overnight.
- Reference example 37 The compound of Reference Example 37 was obtained by using the corresponding raw material compound according to the method described in Reference Example 36.
- Reference example 39-41 The compounds of Reference Examples 39 to 41 were obtained by using the corresponding raw material compounds according to the method described in Reference Example 38.
- Reference example 42 tert-butyl cis-3,4-diazidoazepan-1-carboxylate Sodium azide (1.41 g) was added to a dimethylformamide solution (5 mL) of the compound (1.25 g) of Reference Example 41, and the mixture was stirred at 65 ° C. for 4 hours and at 70 ° C. for 8 hours. Dimethyl sulfoxide (3 mL) was added, and the mixture was stirred at 90 ° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
- Reference example 43 The compound of Reference Example 43 was obtained by using the corresponding raw material compound according to the method described in Reference Example 42.
- Reference example 45 The compound of Reference Example 45 was obtained by using the corresponding raw material compound according to the method described in Reference Example 44.
- Reference example 49-57 The compounds of Reference Examples 49 to 57 were obtained by using the corresponding raw material compounds according to the methods described in Reference Example 1 and Reference Example 2.
- Reference example 58-66 According to the method described in Reference Example 8, the compounds of Reference Examples 58 to 66 were obtained using the corresponding raw material compounds.
- Reference examples 67 and 68 The compounds of Reference Examples 67 and 68 were obtained using the corresponding raw material compounds according to the method described in Reference Example 14.
- Reference example 70 Methyl 2,6-Anhydro-3-deoxy-D-ribo-hexonate Reference Example 69 was added to a 5% hydrogen chloride methanol solution (30 mL) at room temperature, and the mixture was stirred overnight under reflux. After cooling the reaction mixture to 0 ° C., the resulting insoluble material was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (2.82 g).
- Reference example 72 2,6-Anhydro-4,5-O-Benzylidene-3-deoxy-D-ribo-hexitol Sodium borohydride (2.25 g) was added to a methanol solution (40 mL) of Reference Example 71 (3.93 g) under ice-cooling, and the mixture was stirred under ice-cooling for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure.
- Reference example 74 2,6-Anhydro-4,5-O-Benzylidene-1,3-dideoxy-1-fluoro-D-ribo-hexitol Diisopropylethylamine (3.44 mL) and diethylaminosulfur trifluoride (1.04 mL) were added to a dichloromethane solution (33 mL) of Reference Example 72 (10.4 g) under ice-cooling, and the mixture was stirred under reflux for 19 hours. Further, diisopropylethylamine (1.72 mL) and diethylaminosulfur trifluoride (0.52 mL) were added at room temperature, and the mixture was stirred under reflux for 2 hours.
- Reference example 76 3,7-Anhydro-5,6-O-benzylidene-1,2,4-trideoxy-D-ribo-hept-1-initol Potassium carbonate (0.979 mg) and dimethyl (1-diazo-2-oxopropyl) phosphonate (0.638 mL) were added to a methanol solution (35 mL) of Reference Example 75 (0.83 g) at room temperature, and at room temperature. Stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure.
- Reference example 79 The compound of Reference Example 79 was obtained by using the corresponding raw material compound according to the method described in Reference Example 78.
- Reference example 80 3,7-Anhydro-1,2,4-trideoxy-D-ribo-heptitol 10% Palladium on carbon (95 mg) was added to a methanol solution (18 mL) of Reference Example 76 (410 mg) at room temperature, and the mixture was stirred overnight under a room temperature hydrogen atmosphere. The reaction mixture was filtered through cerite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (240 mg).
- Reference examples 81-83 According to the method described in Reference Example 38, the compounds of Reference Examples 81 to 83 were obtained using the corresponding raw material compounds.
- Reference example 84-86 According to the method described in Reference Example 42, the compounds of Reference Examples 84 to 86 were obtained using the corresponding raw material compounds.
- Reference example 87-89 According to the method described in Reference Example 44, the compounds of Reference Examples 87 to 89 were obtained using the corresponding raw material compounds.
- Reference example 90 tert-butyl 3-butene-1-yl (1- (hydroxymethyl) cyclopropyl) carbamate Potassium carbonate (4.56 g), sodium iodide (4.95 g) and 4-bromo-1-butene (3.02 mL) were added to an acetonitrile solution (50 mL) of (1-aminocyclopropyl) methanol at room temperature, and 85 The mixture was stirred at ° C for 12.5 hours. The reaction mixture was cooled to room temperature, filtered and concentrated.
- Reference example 94 The compound of Reference Example 94 was obtained by using the corresponding raw material compound according to the method described in Reference Example 93.
- Reference examples 96 and 97 The compounds of Reference Examples 96 and 97 were obtained using the corresponding raw material compounds according to the method described in Reference Example 95.
- Reference example 100 tert-butyl (2S) -2-methyl-4-[(trifluoromethanesulfonyl) oxy] -3,6-dihydropyridine-1 (2H) -carboxylate
- Reference example 101 tert-butyl (6S) -6-methyl-4-[(trifluoromethanesulfonyl) oxy] -3,6-dihydropyridine-1 (2H) -carboxylate
- Lithium diisopropylamide (1.1M tetrahydrofuran solution, 6.6 mL) in tetrahydrofuran (7 mL) and tert-butyl (S) -2-methyl-4-oxopiperidine-1-carboxylate (1.20 g) in tetrahydrofuran (1.20 g).
- Reference examples 102 and 103 The compounds of Reference Examples 102 and 103 were obtained by using the corresponding raw material compounds according to the methods described in Reference Examples 100 and 101.
- Reference examples 106 and 107 The compounds of Reference Examples 106 and 107 were obtained using the corresponding raw material compounds according to the methods described in Reference Examples 104 and 105.
- Reference example 108 The compound of Reference Example 108 was obtained by using the corresponding raw material compound according to the method described in Reference Example 20.
- Reference example 109 tert-butyl rac- (3R, 4R, 5R) -3- ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ -4,5-dihydroxypiperidine-1-carboxylate 4-Methylmorpholine-4-oxide monohydrate (2.68 g) and osmium tetroxide (immobilization) in a water / acetone / acetonitrile solution (15 mL / 15 mL / 15 mL) of the compound (4.76 g) of Reference Example 108. Catalyst I) (2.06 g) was added at room temperature and stirred at room temperature for 16 hours.
- Reference example 110 1,6-Anhydro-2,3-dideoxy-D-erythro-2-hexenitol A catalytic amount of 10% palladium carbon was added to a methanol solution (50 mL) of the compound (2.36 g) of Reference Example 97 at room temperature, and the mixture was stirred overnight at room temperature under a normal pressure hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (1.00 g).
- Reference example 111-118 According to the method described in Reference Example 38, the compounds of Reference Examples 111 to 118 were obtained using the corresponding raw material compounds.
- Reference example 120 The compound of Reference Example 120 was obtained by using the corresponding raw material compound according to the method described in Reference Example 119.
- Reference examples 121-132 According to the method described in Reference Example 38, the compounds of Reference Examples 121 to 132 were obtained using the corresponding raw material compounds.
- Reference example 133-146 According to the method described in Reference Example 42, the compounds of Reference Examples 133 to 146 were obtained using the corresponding raw material compounds.
- Reference example 152-166 The compounds of Reference Examples 152 to 166 were obtained by using the corresponding raw material compounds according to the method described in Reference Example 44 or Reference Example 151.
- Triethylamine (1.59 mL) and (Boc) 2 O (2.64 mL) were added to a solution of the obtained crude product in methanol (28 mL) at room temperature, and the mixture was stirred overnight at room temperature.
- the reaction mixture was concentrated under reduced pressure and then purified by silica gel chromatography (hexane / ethyl acetate) to give the title compound (314 mg).
- Reference example 168-206 The compounds of Reference Examples 168 to 206 were obtained by using the corresponding raw material compounds according to the methods described in Reference Example 1, Reference Example 2 and Reference Example 24.
- Reference example 208-248 The compounds of Reference Examples 208 to 248 were obtained by using the corresponding raw material compounds according to the methods described in Reference Example 8, Reference Example 26 and Reference Example 47.
- Reference example 249-268 The compounds of Reference Examples 249 to 268 were obtained by using the corresponding raw material compounds according to the method described in Reference Example 14.
- Reference example 269 The compound of Reference Example 269 was obtained by using the corresponding raw material compound according to the method described in Reference Example 28.
- Reference example 271 tert-butyl (3aS, 6aR) -3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -2-oxohexahydro-1H-flo [3,4] -D] Imidazole-1-carboxylate
- Reference example 272 tert-butyl (3aR, 6aS) -3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -2-oxohexahydro-1H-flo [3,4] -D] Imidazole-1-carboxylate
- the compound of Reference Example 270 (465 mg) was optically fractionated under the following conditions of supercritical fluid chromatography, and the title compound (Reference Example 271: 160 mg-first peak: 2.01 min, Reference Example 272: 160 mg-second peak: 4.03 min) was obtained.
- the reaction mixture was concentrated under reduced pressure and then purified by silica gel chromatography (hexane / ethyl acetate) to obtain a Boc body (70.0 mg).
- Triethylamine (0.048 mL) and methanesulfonyl chloride (0.024 mL) were added to a dichloromethane solution (6 mL) of the obtained Boc body (70.0 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product (106 mg).
- Reference example 274 The compound of Reference Example 274 was obtained by using the corresponding raw material compound according to the method described in Reference Example 273.
- Reference example 275 1,4-Anhydro-5-O- [tert-butyl (dimethyl) silyl] -2,3-bis-O- (trifluoromethanesulfonyl) -D-ribitol (2R, 3S, 4S) -2-[ ⁇ (tert-butyldimethylsilyl) oxy ⁇ methyl] Tetrahydrofuran-3,4-diol (4.00 g) in dichloromethane solution (322 mL) with pyridine (7.81 mL) Trifluoromethanesulfonic anhydride (8.16 mL) was added under ice-cooling and stirred under ice-cooling for 1 hour.
- Reference example 276 2,5-Anhydro-1-O- [tert-butyl (dimethyl) silyl] -D-arabinitol 18-Crown-6 (7.82 g) and cesium acetate (7.91 g) were added to a dimethylformamide solution (92 mL) of the compound of Reference Example 275 (7.04 g) at room temperature, and the mixture was stirred at 40 ° C. for 13 hours. .. Cesium acetate (7.91 g) was added, and the mixture was further stirred at 40 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the mixture was extracted with ethyl acetate.
- Reference example 277 The compound of Reference Example 277 was obtained by using the corresponding raw material compound according to the method described in Reference Example 38.
- Reference example 278 The compound of Reference Example 278 was obtained by using the corresponding raw material compound according to the method described in Reference Example 42.
- Reference example 279 The compound of Reference Example 279 was obtained by using the corresponding raw material compound according to the method described in Reference Example 44.
- Reference Examples 280 and 281 The compounds of Reference Examples 280 and 281 were obtained by using the corresponding raw material compounds according to the methods described in Reference Example 1 and Reference Example 2.
- Reference examples 282 and 283 The compounds of Reference Examples 282 and 283 were obtained using the corresponding raw material compounds according to the method described in Reference Example 47.
- Reference examples 284 and 285 The compounds of Reference Examples 284 and 285 were obtained using the corresponding raw material compounds according to the method described in Reference Example 38.
- Reference example 286 The compound of Reference Example 286 was obtained by using the corresponding raw material compound according to the method described in Reference Example 42.
- Reference example 287 The compound of Reference Example 287 was obtained by using the corresponding raw material compound according to the method described in Reference Example 44.
- Reference example 288 The compound of Reference Example 288 was obtained by using the corresponding raw material compound according to the methods described in Reference Example 1 and Reference Example 2.
- Reference example 289 The compound of Reference Example 289 was obtained by using the corresponding raw material compound according to the method described in Reference Example 47.
- Reference example 290 The compound of Reference Example 290 was obtained by using the corresponding raw material compound according to the method described in Reference Example 77.
- Example 1 cis-3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) octahydro-2H-imidazole [4,5-c] pyridin-2-one Trifluoroacetic acid (3 mL) was added to the compound (114 mg) of Reference Example 14, and the mixture was stirred for 11 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (62 mg).
- Examples 2 to 6 The compounds of Examples 2 to 6 were obtained by using the corresponding raw material compounds according to the method described in Example 1.
- Example 7 cis-3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5-methyloctahydro-2H-imidazole [4,5-c] pyridin-2- on A 37% formaldehyde solution (0.02 mL) and methanol (1 mL) were added to a methanol (2 mL) solution of the compound (21.8 mg) of Example 1, and the mixture was stirred for 10 minutes. Sodium borohydride triacetoxyboron (50 mg) was added and stirred for 20 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform.
- Example 8 cis-3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5- (2-methoxyethyl) octahydro-2H-imidazole [4,5-c] Pyridine-2-on 2-Chloroethylmethyl ether (0.036 mL), potassium iodide (66 mg) and potassium carbonate (111 mg) were added to a suspension of the compound (32 mg) of Example 1 in acetonitrile (1 mL), and the mixture was stirred at 80 ° C. for 15 hours. did. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform.
- Examples 9-19 The compounds of Examples 9 to 19 were obtained by using the corresponding raw material compounds according to the method described in Example 7 or Example 8.
- Example 20 cis-5-Acetyl-3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) Octahydro-2H-imidazole [4,5-c] Pyridine-2-one
- Triethylamine (0.028 mL) and acetic anhydride (0.011 mL) were added to a chloroform solution (2 mL) of the compound of Example 1 (32 mg), and the mixture was stirred overnight.
- Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform / ethanol (3/1). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure.
- Example 21 (3aR, 7aR) -1- (2H- [1,3] dioxolo [4,5-e] [1,3] benzothiazole-7-yl) hexahydropyrano [3,4-d] imidazole-2 (3H) -On A 4M ethyl acetate solution of hydrogen chloride (5 mL) was added to an ethyl acetate solution (5 mL) of the compound (759 mg) of Reference Example 47, and the mixture was stirred overnight at room temperature. Hexane was added to the reaction mixture, the resulting solid was collected by filtration, the hexane was washed, and the mixture was dried under reduced pressure.
- Triethylamine (1.41 mL) and di (N-succinimidyl) (519 mg) were added to a dimethylformamide solution (20 mL) of the obtained solid (668 mg), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (364 mg).
- Example 22 (4R, 5R) -1- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5-[(dimethylamino) methyl] -4-methylimidazolidine- 2-on Dimethylamine (2.0 M tetrahydrofuran solution) (0.31 mL), potassium iodide (26.2 mg), and potassium carbonate (55.6 mg) were added to an acetonitrile solution (3 mL) of the compound (59.4 mg) of Reference Example 39. , 60 ° C. for 15 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with chloroform-methanol (10: 1).
- Examples 23-26 The compounds of Examples 23 to 26 were obtained by using the corresponding raw material compounds according to the method described in Example 22.
- Example 27 (3aS, 7aR) -3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5-methyloctahydro-2H-imidazole [4,5-c] Pyridine-2-on
- Example 28 (3aR, 7aS) -3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5-methyloctahydro-2H-imidazole [4,5-c] Pyridine-2-on
- the compound of Example 7 (30.0 mg) was optically fractionated under the following conditions, and the title compound (Example 27: 12.2 mg-first peak: 15.3 min, Example 28: 8.1 mg-second peak: 16.4 min) was obtained.
- Examples 29 and 30 The compounds of Examples 29 and 30 were obtained using the corresponding raw material compounds according to the method described in Example 1.
- Example 31 cis-5-cyclopropyl-3- (7,8-dihydro [1,4] dioxyno [2,3-e] [1,3] benzothiazole-2-yl) octahydro-2H-imidazole [4,5-) c] Pyridine-2-on (1-ethoxycyclopropoxy) trimethylsilane (0.121 mL), acetic acid (0.172 mL) and sodium cyanoborohydride in a methanol / tetrahydrofuran solution (1.5 mL / 1.2 mL) of the compound (100 mg) of Example 29. (94 mg) was added, and the mixture was stirred at 60 ° C. for 3 hours.
- Example 32 The compound of Example 32 was obtained by using the corresponding raw material compound according to the method described in Example 31.
- Example 33 (3aS, 7aR) -5-Cyclopropyl-3- (7,8-dihydro [1,4] dioxyno [2,3-e] [1,3] benzothiazole-2-yl) octahydro-2H-imidazole [ 4,5-c] Pyridine-2-one
- Example 34 (3aR, 7aS) -5-Cyclopropyl-3- (7,8-dihydro [1,4] dioxyno [2,3-e] [1,3] benzothiazole-2-yl) octahydro-2H-imidazole [ 4,5-c] Pyridine-2-one
- the compound of Example 31 (104 mg) was optically fractionated under the following conditions to obtain the title compound (Example 33: 37 mg-first peak: 13.0 min, Example 34: 36 mg-second peak: 14.9 min).
- Example 35 (3aS, 7aR) -5-Cyclopropyl-3- (2H- [1,3] dioxolo [4,5-e] [1,3] benzothiazole-7-yl) Octahydro-2H-imidazole [4,5 -C] Pyridine-2-on
- Example 36 (3aR, 7aS) -5-Cyclopropyl-3- (2H- [1,3] dioxolo [4,5-e] [1,3] benzothiazole-7-yl) Octahydro-2H-imidazole [4,5 -C] Pyridine-2-on
- the compound of Example 32 (85.0 mg) was optically fractionated under the following conditions, and the title compound (Example 35: 37.1 mg-first peak: 10.7 min, Example 36: 36.4 mg-second peak: 12.3 min) was obtained.
- Examples 37-43 The compounds of Examples 37 to 43 were obtained by using the corresponding raw material compounds according to the method described in Reference Example 14.
- Example 44 The compound of Example 44 was obtained by using the corresponding raw material compound according to the method described in Reference Example 14.
- Examples 45-66 The compounds of Examples 45 to 66 were obtained by using the corresponding raw material compounds according to the method described in Example 1.
- Examples 67-108 The compounds of Examples 67 to 108 were obtained by using the corresponding raw material compounds according to the method described in Example 7 or Example 8.
- Example 109 (3aS, 7aR) -5-Cyclopropyl-3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) Octahydro-2H-imidazole [4,5-c] Pyridine-2-on
- Example 110 (3aR, 7aS) -5-Cyclopropyl-3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) Octahydro-2H-imidazole [4,5-c] Pyridine-2-on
- the compound of Example 98 (12.0 mg) was optically fractionated under the following conditions, and the title compound (Example 109: 1.5 mg-first peak: 9.40 min, Example 110: 1.1 mg-second peak: 10.8 min) was obtained.
- Example 111 [(3aS, 7aR) -3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -2-oxooctahydro-5H-imidazole [4,5-c] ] Pyridine-5-yl] acetonitrile
- Example 112 [(3aR, 7aS) -3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -2-oxooctahydro-5H-imidazole [4,5-c] ] Pyridine-5-yl] acetonitrile
- the compound of Example 100 (30.0 mg) was optically resolved under the following conditions, and the title compound (Example 111: 13.8 mg-First Peak: 13.0 min, Example 112: 12.2 mg-Second Peak: 14) was optically resolved.
- Example 113 (3aS, 7aR) -3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5- (2-propyne-1-yl) octahydro-2H-imidazole [4,5-c] Pyridine-2-one
- Example 114 (3aR, 7aS) -3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -5- (2-propyne-1-yl) octahydro-2H-imidazole [4,5-c] Pyridine-2-one
- the compound of Example 99 (30.0 mg) was optically resolved under the following conditions, and the title compound (Example 113: 15.4 mg-First Peak: 10.2 min, Example 114: 13.7 mg-Second Peak: 11) was optically resolved.
- Examples 115-118 The compounds of Examples 115 to 118 were obtained by using the corresponding raw material compounds according to the method described in Example 19.
- Examples 119-124 The compounds of Examples 119 to 124 were obtained by using the corresponding raw material compounds according to the method described in Example 21.
- Examples 125-140 According to the method described in Reference Example 14, the compounds of Examples 125 to 140 were obtained using the corresponding raw material compounds.
- Examples 141-143 According to the method described in Reference Example 70, the compounds of Examples 141 to 143 were obtained using the corresponding raw material compounds.
- Examples 144-147 According to the method described in Reference Example 72, the compounds of Examples 144 to 147 were obtained using the corresponding raw material compounds.
- Example 148 The compound of Example 148 was obtained by using the corresponding raw material compound according to the method described in Reference Example 75.
- Example 149 The compound of Example 149 was obtained by using the corresponding raw material compound according to the method described in Reference Example 76.
- Example 150 (3aR, 7aR) -1- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -6-hydroxyhexahydropyrano [3,4-d] imidazole- 2 (3H) -on 1N Hydrochloric acid (4 mL) was added to a 1,4-dioxane solution (3 mL) of the compound (53.0 mg) of Example 129 at room temperature, and the mixture was stirred at room temperature for 1 hour and at 60 ° C. for 2 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate.
- Example 151 (3aR, 7aR) -1- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -6-fluorohexahydropyrano [3,4-d] imidazole- 2 (3H) -on Diethylaminosulfur trifluoride (0.041 mL) was added to a solution of Example 150 (69.0 mg) in dichloromethane / 1,4-dioxane (6 mL / 9 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 15 minutes.
- Example 152 The compound of Example 152 was obtained by using the corresponding raw material compound according to the method described in Reference Example 75.
- Examples 153 and 154 The compounds of Examples 153 and 154 were obtained using the corresponding raw material compounds according to the method described in Reference Example 147.
- Examples 155 and 156 The compounds of Examples 155 and 156 were obtained using the corresponding raw material compounds according to the method described in Reference Example 14.
- Examples 157 and 158 The compounds of Examples 157 and 158 were obtained using the corresponding raw material compounds according to the method described in Reference Example 147.
- Example 159 The compound of Example 159 was obtained by using the corresponding raw material compound according to the method described in Reference Example 74.
- Example 160 The compound of Example 160 was obtained by using the corresponding raw material compound according to the method described in Reference Example 14.
- Example 161 (3aR, 6R, 6aS) -1- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -6-methyltetrahydro-1H-flo [3,4-d] ] Imidazole-2 (3H) -on Reference Example 290 (1.0 mg) in tetrahydrofuran (3 mL) was added with tetrabutylammonium fluoride 1.0 Mtetrahydrofuran solution (0.024 mL) at room temperature, and the mixture was stirred at room temperature for 2 days.
- Example 162 [(3aS, 4R, 6aR) -3- (7,8-dihydroflo [3,2-e] [1,3] benzothiazole-2-yl) -2-oxohexahydro-1H-flo [3,4] -D] Imidazole-4-yl] acetonitrile
- Potassium cyanide (4.0 mg) was added to a dimethyl sulfoxide solution (2 mL) of Reference Example 285 (20.0 mg) at room temperature, and the mixture was stirred at 80 ° C. for 1 hour. Further, potassium cyanide (16.5 mg) was added, and the mixture was stirred at 80 ° C.
- 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.
- 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. .. This result indicates that the test compound (compound (1) of the present invention) has a strong DYRK inhibitory activity.
- mice were aged 8 to 12 weeks (B6C3F1, female, Charles River, Japan) were used.
- Example compounds suspended in 0.5% methylcellulose solution or 0.5% methylcellulose solution were orally administered once or repeatedly at 10 mL / kg to mice, and after the day after the final administration, under isofluran anesthesia from the posterior vena cava.
- the collected blood was anti-coagulated with a blood collection tube containing EDTA-2K, and the reticulocyte count was quantified with a multi-item automatic blood cell analyzer (manufactured by Compound). [Evaluation results] It was confirmed that the compound of the present invention exhibits safety in the medicinal region.
- 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, and tumors such as brain tumors. Further, as an inhibitor of DYRK1B, it is useful as a prophylactic or therapeutic drug (pharmaceutical composition) for tumors 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.
- 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.
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Abstract
Description
下記式(1):
A1は、酸素原子又は窒素原子(=N-)を表し、
A2は、CRB、CRCRD、酸素原子又はNRA1を表し、
L1は、置換されていてもよいメチレン、置換されていてもよいエチレン、置換されていてもよいメチン、置換されていてもよいエタンジイリデン、=N-又はNRA2を表し、
RA1、RA2、RB、RCおよびRDは、それぞれ独立して、水素原子又は置換されていてもよいC1-6アルキルを表し、
R1は、水素原子、ハロゲン原子又は置換されていてもよいC1-6アルキルを表し、
Xは、炭素原子又は窒素原子を表し、
L2は、置換されていてもよいC1-4アルキレンを表し、
REは、置換されていてもよいC1-6アルキルを表し、
Zは、-NR2R3又は-OR7を表し、
R7は、置換されていてもよいC1-6アルキル、又はR4とともに形成される、置換されていてもよいC1-7アルキレンを表し、ここにおいて、R4およびR7が、それぞれが結合する炭素原子および酸素原子と一緒になって、置換されていてもよい5-11員の飽和複素環を形成し、
R2は、水素原子、置換されていてもよいC1-6アルキル、C(O)-RE、C3-10シクロアルキル、C2-6アルキニル又は4-11員の飽和複素環の環状基を表し、
R3は、水素原子、置換されていてもよいC1-6アルキル又はC(O)-REを表し、
R4は、置換されていてもよいC1-6アルキルを表し、
ここにおいて、R2およびR3が、これらが結合する窒素原子と一緒になって、置換されていてもよい4-11員の飽和複素環を形成していてもよく、あるいは、R3およびR4が、それぞれが結合する窒素原子および炭素原子と一緒になって、置換されていてもよい4-11員の飽和複素環を形成していてもよく、若しくは、前記R2、R3および窒素原子で構成される飽和複素環上の任意の炭素原子およびR4が一緒になって、4-11員の飽和複素環を形成していてもよい。]で表される化合物(本明細書において、「化合物(1)」又は「式(1)で表される化合物」と称することがある。)又はその薬学的に許容される塩。
Zが、-NR2R3を表し、R2およびR3が、それぞれ独立して、水素原子、置換されていてもよいC1-6アルキル又はC(O)-REを表し、ここにおいて、R2およびR3が、これらが結合する窒素原子と一緒になって、置換されていてもよい4-8員の飽和複素環を形成していてもよい、項1に記載の化合物又はその薬学的に許容される塩。
Zが、-NR2R3を表し、R3およびR4が、それぞれが結合する窒素原子および炭素原子と一緒になって、置換されていてもよい4-8員の飽和複素環を形成する、項1に記載の化合物又はその薬学的に許容される塩。
R1が、水素原子である、項1-3のいずれか一項に記載の化合物又はその薬学的に許容される塩。
Xが、炭素原子である、項1-4のいずれか一項に記載の化合物又はその薬学的に許容される塩。
A1が、酸素原子であり、A2がメチレンであり、L1がメチレンである、項5に記載の化合物又はその薬学的に許容される塩。
式(1)が、下記式(1a):
A2は、置換されていてもよいメチレン又は酸素原子を表し、
L1は、置換されていてもよいメチレン又は置換されていてもよいエチレンを表し、
L2は、置換されていてもよいC1-4アルキレンを表し、
R2およびR3は、それぞれ独立して、水素原子、置換されていてもよいC1-6アルキル又はC(O)-REを表し、ここにおいて、R2およびR3が、これらが結合する窒素原子と一緒になって、置換されていてもよい4-8員の飽和複素環を形成していてもよく、
REは、置換されていてもよいC1-6アルキルを表し、
R4は、置換されていてもよいC1-6アルキルである。]で表される項1、2、4、5又は6に記載の化合物又はその薬学的に許容される塩。
R2およびR3が、それぞれ独立して、置換されていてもよいC1-6アルキルである、項7に記載の化合物又はその薬学的に許容される塩。
R2およびR3が、これらが結合する窒素原子と一緒になって、置換されていてもよい4-8員の飽和複素環を形成する、項7に記載の化合物又はその薬学的に許容される塩。
L2が、C1-3アルキレンである、項7-9のいずれか一項に記載の化合物又はその薬学的に許容される塩。
式(1)が、下記式(1b):
A2は、置換されていてもよいメチレン又は酸素原子を表し、
L1は、置換されていてもよいメチレン又は置換されていてもよいエチレンを表し、
lおよびmは、それぞれ独立して、1、2又は3を表し、ここにおいて、lとmの合計が5以下であり、
nは、1、2、3又は4を表し、
R2は、水素原子、置換されていてもよいC1-6アルキル、C3-10シクロアルキル又はC(O)-REを表し、
REは、置換されていてもよいC1-6アルキルを表し、
RFは、水素原子、ハロゲン原子又は置換されていてもよいC1-6アルキルを表し、
nが2、3又は4の場合、RFは同一でも異なっていてもよく、また同一炭素原子上の2個のRFが、それぞれ結合する炭素原子と一緒になって4-8員の飽和複素環又は3-8員の飽和炭素環からなるスピロ環を形成していてもよく、あるいは異なる炭素原子上の2個のRFが、結合して架橋を形成していてもよい。]で表される項1、3、4、5又は6に記載の化合物又はその薬学的に許容される塩。
R2が、水素原子、置換されていてもよいC1-6アルキル又はC3-10シクロアルキルである、項11に記載の化合物又はその薬学的に許容される塩。
R2が、置換されていてもよいC1-6アルキルである、項11に記載の化合物又はその薬学的に許容される塩。
lおよびmが、それぞれ独立して、1又は2である、項11-13のいずれか一項に記載の化合物又はその薬学的に許容される塩。
Zが-OR7であって、R4およびR7が、それぞれが結合する炭素原子および酸素原子と一緒になって、置換されていてもよい5-8員の飽和複素環を形成する、項1に記載の化合物又はその薬学的に許容される塩。
式(1)が、下記式(1c):
A2は、置換されていてもよいメチレン又は酸素原子を表し、
L1は、置換されていてもよいメチレン又は置換されていてもよいエチレンを表し、
pおよびqは、それぞれ独立して、1、2又は3を表し、ここにおいて、pとqの合計が5以下であり、
tは、1、2、3又は4を表し、
RGは、水素原子、ハロゲン原子、置換されていてもよいC1-6アルキル、置換されていてもよいC1-6アルコキシ又はCN基を表し、
tが2、3又は4の場合、RGは同一でも異なっていてもよく、また同一炭素原子上の2個のRGが、それぞれ結合する炭素原子と一緒になって4-8員の飽和複素環又は3-8員の飽和炭素環からなるスピロ環を形成していてもよく、あるいは異なる炭素原子上の2個のRGが、結合して架橋を形成していてもよい。]で表される項1又は15に記載の化合物又はその薬学的に許容される塩。
以下の化合物の群から選択される、項1-16のいずれか一項に記載の化合物又はその薬学的に許容される塩:
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例7);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-メトキシエチル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例8);
cis-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例9);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-エチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例11);
cis-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルヘキサヒドロピロロ[3,4-d]イミダゾールl-2(1H)-オン(実施例14);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(プロパン-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例15);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例17);
(3aS,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例19);
(3aR,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例21);
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチル-5-[(モルホリン-4-イル)メチル]イミダゾリジン-2-オン(実施例23);
(4R,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチル-5-[(モルホリン-4-イル)メチル]イミダゾリジン-2-オン(実施例24);
(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例28);
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例34);
(3aR,7aS)-5-シクロプロピル-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例36);
(3aR,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例37);
(3aR,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メチルヘキサヒドロピラノ[3,4ーd]イミダゾール-2(3H)-オン(実施例38);
(3aR,6S,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-メチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例39);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例40);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例41);
(3aR,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例42);
(3aR,6S,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例43);
(4S,5S)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(メトキシメチル)-4-メチルイミダゾリジン-2-オン(実施例44);
(3aR,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)テトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例65);
rac-(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例71);
rac-(3aR,7aS)-5-シクロブチル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例72);
rac-(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例73);
rac-(3aR,7aS)-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例76);
rac-(3aR,7aS)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例77);
rac-(3aR,7aS)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例78);
rac-(3aR,7aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例79);
rac-(3aR,7aS)-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例80);
rac-(3aR,7aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例81);
rac-(3aR,8aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-メチルオクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例85);
rac-(3aR,8aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-(オキセタン-3-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例86);
(3aS,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5,6-ジメチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例93);
rac-(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例98);
rac-(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例99);
rac-[(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-イル]アセトニトリル(実施例100);
rac-(3aR,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)ヘキサヒドロピロロ[3,4-d]イミダゾール-2(1H)-オン(実施例102);
rac-[(3aR,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロピロロ[3,4-d]イミダゾール-5(1H)-イル]アセトニトリル(実施例103);
rac-(3aR,8aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例104);
rac-(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例105);
rac-[(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロイミダゾ[4,5-c]アゼピン-5(1H)-イル]アセトニトリル(実施例106);
rac-(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2,2,2-トリフルオロエチル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例107);
rac-(3aR,7aS)-5-(2,2-ジフルオロエチル)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例108);
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例110);
[(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-イル]アセトニトリル(実施例112);
(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例114);
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-{[(3S)-3-フルオロピロリジン-1-イル]メチル}-4-メチルイミダゾリジン-2-オン(実施例115);
(4S,5R)-5-[(3,3-ジフルオロアゼチジン-1-イル)メチル]-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチルイミダゾリジン-2-オン(実施例116);
(4S,5R)-5-[(3,3-ジフルオロピロリジン-1-イル)メチル]-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチルイミダゾリジン-2-オン(実施例117);
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-[(3-フルオロアゼチジン-1-イル)メチル]-4-メチルイミダゾリジン-2-オン(実施例118);
rac-(3aR,7aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例120);
rac-(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例121);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例122);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6,6-ジメチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例124);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例127);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メトキシヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例129);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例131);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例133);
(3aR,8aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロ-1H-オキセピノ[3,4-d]イミダゾール-2(3H)-オン(実施例135);
(3aR,6S,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例138);
(3aR,6S,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル]-6-メチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例139);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル]-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例140);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(ヒドロキシメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例144);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-(ヒドロキシメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例146);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-6-(ヒドロキシメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例147);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-エチニルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例149);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-フルオロヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例151);
(3aR,6S,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(ヒドロキシメチル)テトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例157);
(3aR,6S,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)テトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例159);
(3aR,6R,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メチルテトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例161);および
[(3aS,4R,6aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロ-1H-フロ[3,4-d]イミダゾール-4-イル]アセトニトリル(実施例162)。
項1-17のいずれか一項に記載の化合物又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。
項1-17のいずれか一項に記載の化合物又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。
項1-17のいずれか一項に記載の化合物又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。
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、慢性腎疾患又は骨吸収疾患である、項20に記載の治療剤及び/又は予防剤。
治療が必要な患者に、治療上の有効量の項1-17のいずれか一項に記載の化合物、又はその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。
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、項1-17のいずれか一項に記載の化合物、又はその薬学的に許容される塩の使用。
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、項1-17のいずれか一項に記載の化合物、又はその薬学的に許容される塩。
項18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。
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、認知症症状進行の治療又は認知症発症の予防あるいは脳腫瘍、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、慢性腎疾患又は骨吸収疾患を治療するための、項18に記載の医薬。
Zが-OR7の場合において、「R4およびR7が、それぞれが結合する炭素原子および酸素原子と一緒になって形成される5-11員の飽和複素環」とは、その環状の構成原子として当該酸素原子以外の1又は2以上のヘテロ原子を含む、単環又は2環の飽和複素環を意味し、一部不飽和結合を有するもの及び架橋された構造のものも含まれる。当該「R4およびR7が、それぞれが結合する炭素原子および酸素原子と一緒になって形成される5-11員の飽和複素環」として、好ましくは「5-8員の飽和複素環」が挙げられる。当該「5-8員の飽和複素環」の具体例として、例えば、テトラヒドロフラン環、テトラヒドロピラン環、オキセパン環、オキソカン環等が挙げられる。「5-11員の飽和複素環」の具体例としては、例えば、前記「5-8員の飽和複素環」の具体例として挙げたものに加え、オキソナン環、オキセカン環、オキサシクロウンデカン環等が挙げられる。
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-メトキシエチル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例8);
cis-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例9);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-エチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例11);
cis-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルヘキサヒドロピロロ[3,4-d]イミダゾールl-2(1H)-オン(実施例14);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(プロパン-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例15);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例17);
(3aS,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例19);
(3aR,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例21);
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチル-5-[(モルホリン-4-イル)メチル]イミダゾリジン-2-オン(実施例23);
(4R,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチル-5-[(モルホリン-4-イル)メチル]イミダゾリジン-2-オン(実施例24);
(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例28);
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例34);
(3aR,7aS)-5-シクロプロピル-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例36);
(3aR,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例37);
(3aR,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メチルヘキサヒドロピラノ[3,4ーd]イミダゾール-2(3H)-オン(実施例38);
(3aR,6S,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-メチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例39);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例40);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例41);
(3aR,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例42);
(3aR,6S,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例43);
(4S,5S)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(メトキシメチル)-4-メチルイミダゾリジン-2-オン(実施例44);
(3aR,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)テトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例65);
rac-(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例71);
rac-(3aR,7aS)-5-シクロブチル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例72);
rac-(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例73);
rac-(3aR,7aS)-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例76);
rac-(3aR,7aS)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例77);
rac-(3aR,7aS)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例78);
rac-(3aR,7aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例79);
rac-(3aR,7aS)-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例80);
rac-(3aR,7aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例81);
rac-(3aR,8aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-メチルオクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例85);
rac-(3aR,8aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-(オキセタン-3-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例86);
(3aS,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5,6-ジメチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例93);
rac-(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例98);
rac-(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例99);
rac-[(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-イル]アセトニトリル(実施例100);
rac-(3aR,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)ヘキサヒドロピロロ[3,4-d]イミダゾール-2(1H)-オン(実施例102);
rac-[(3aR,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロピロロ[3,4-d]イミダゾール-5(1H)-イル]アセトニトリル(実施例103);
rac-(3aR,8aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例104);
rac-(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例105);
rac-[(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロイミダゾ[4,5-c]アゼピン-5(1H)-イル]アセトニトリル(実施例106);
rac-(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2,2,2-トリフルオロエチル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例107);
rac-(3aR,7aS)-5-(2,2-ジフルオロエチル)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例108);
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例110);
[(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-イル]アセトニトリル(実施例112);
(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例114);
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-{[(3S)-3-フルオロピロリジン-1-イル]メチル}-4-メチルイミダゾリジン-2-オン(実施例115);
(4S,5R)-5-[(3,3-ジフルオロアゼチジン-1-イル)メチル]-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチルイミダゾリジン-2-オン(実施例116);
(4S,5R)-5-[(3,3-ジフルオロピロリジン-1-イル)メチル]-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチルイミダゾリジン-2-オン(実施例117);
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-[(3-フルオロアゼチジン-1-イル)メチル]-4-メチルイミダゾリジン-2-オン(実施例118);
rac-(3aR,7aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例120);
rac-(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例121);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例122);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6,6-ジメチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例124);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例127);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メトキシヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例129);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例131);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例133);
(3aR,8aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロ-1H-オキセピノ[3,4-d]イミダゾール-2(3H)-オン(実施例135);
(3aR,6S,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例138);
(3aR,6S,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル]-6-メチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例139);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル]-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例140);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(ヒドロキシメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例144);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-(ヒドロキシメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例146);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-6-(ヒドロキシメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例147);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-エチニルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例149);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-フルオロヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例151);
(3aR,6S,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(ヒドロキシメチル)テトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例157);
(3aR,6S,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)テトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例159);
(3aR,6R,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メチルテトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例161);および
[(3aS,4R,6aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロ-1H-フロ[3,4-d]イミダゾール-4-イル]アセトニトリル(実施例162)。
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチル-5-[(モルホリン-4-イル)メチル]イミダゾリジン-2-オン(実施例23);
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例34);
(3aR,7aS)-5-シクロプロピル-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例36);
(3aR,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例37);
(3aR,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メチルヘキサヒドロピラノ[3,4ーd]イミダゾール-2(3H)-オン(実施例38);
(3aR,6S,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-メチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例39);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例40);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例41);
(3aR,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例42);
(3aR,6S,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例43);
(4S,5S)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(メトキシメチル)-4-メチルイミダゾリジン-2-オン(実施例44);
rac-(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例73);
rac-(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例98);
rac-(3aR,8aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例104);
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例110);
[(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-イル]アセトニトリル(実施例112);
(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例114);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例122);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6,6-ジメチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例124);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例127);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例131);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例133);
(3aR,6S,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例138);
(3aR,6S,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル]-6-メチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例139);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル]-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例140)
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-エチニルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例149);および
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-フルオロヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例151)。
反応式中の化合物はそれぞれ塩を形成している場合も含み、該塩としては、例えば化合物(1)の塩と同様のものが挙げられる。なお、これらの反応は単なる例示であり、有機合成に習熟している者の知識に基づき、適宜、他の方法で本発明化合物を製造することもできる。
なお、これら官能基を保護した化合物も、前記式(1)の化合物に包含される。
式(1-9)で表される化合物は、例えば、下記に示される方法によって製造される。
化合物(1-3)は、化合物(1-1)を公知の合成法(例えば、Chemical & Pharmaceutical Bulletin, 1406, (2007), Advanced Synthesis & Catalysis, 1643, (2005)等)と類似の方法で化合物(1-2)と反応することにより得ることができる。化合物(1-1)は、公知の合成法(例えば、Bioorganic & Medicinal Chemistry Letters, 28, (2007), J. Org. Chem. 2613, (1986)等)もしくはそれに準じた合成法によって製造されたものを用いることができる。化合物(1-2)は、市販品として又は公知の合成法(例えば、Tetrahedron Letters, 946, (2015), Synlett, 426, (1999)等)もしくはそれに準じた合成法によって製造されたものを用いることができる。
化合物(1-4)は、化合物(1-3)を公知の合成法(例えば、Journal of Organic Chemistry, 8693, (2003), WO2013043001等)と類似の方法で環化することにより製造される。
化合物(1-5)は、化合物(1-4)を公知の合成法(例えば、Organic Letters, 5136, (2015), Bioorganic & Medicinal Chemistry, 822, (2008)等)と類似の方法で環化することにより製造される。
化合物(1-9)は、化合物(1-5)を、不活性溶媒中で、水素化ホウ素化合物と必要に応じて酸の存在下、化合物(1-6)とを反応させることによって得ることができる。化合物(1-6)は、市販品として又は公知の合成法(例えば、US200619965, Journal of Medicinal Chemistry, 3680, (2003)等)もしくはそれに準じた合成法によって製造されたものを用いることができる。
式(2-7)で表される化合物は、例えば、下記に示される方法によって製造される。
化合物(2-2)は、化合物(1-1)と化合物(2-1)を用い、工程1-1に記載の方法に準じて製造される。化合物(2-1)は、公知の合成法(例えば、Chemical Communications 7693, (2015), WO2015061572等)もしくはそれに準じた合成法によって製造されたものを用いることができる。
化合物(2-3)は、化合物(2-2)を用い、工程1-2に記載の方法に準じて製造される。
化合物(2-4)は、化合物(2-3)を用い、保護基の脱保護を経た後に、工程1-3に記載の方法に準じて製造される。
化合物(2-5)は、LGが置換スルホニル基である場合、化合物(2-4)を、保護基の脱保護を行った後に、不活性溶媒中で塩基の存在下、塩化スルホニルと反応させることにより得ることができる。LGがハロゲンである場合、化合物(2-4)を、保護基の脱保護を行った後に、不活性溶媒中でハロゲン化剤と反応させることにより得ることができる。
化合物(2-7)は、化合物(2-5)を、不活性溶媒中で塩基と必要に応じてハロゲン化物の存在下、(2-6)と反応させることにより得ることができる。化合物(2-6)は、市販品として又は公知の合成法(例えば、WO20073965, US2010216812等)もしくはそれに準じた合成法によって製造されたものを用いることができる。
式(1-4)で表される化合物は、例えば、下記に示される方法によっても製造される。
化合物(3-2)は、化合物(1-1)と化合物(3-1)を用い、工程1-1に記載の方法に準じて製造される。化合物(3-1)は、市販品として又は公知の合成法(例えば、WO2008136457, WO2014015905等)もしくはそれに準じた合成法によって製造されたものを用いることができる。
化合物(3-3)は、化合物(3-2)を用い、工程1-2に記載の方法に準じて製造される。
化合物(3-4)は、化合物(3-3)を用い、工程2-4に記載の方法に準じて製造される。
化合物(3-5)は、化合物(3-4)を用い、公知の合成法(例えば、Journal of Medicinal Chemistry 3918, (1995), WO2015177326等)と類似の方法で合成することにより製造される。
化合物(1-4)は、化合物(3-5)を用い、公知の合成法(例えば、Bioorganic & Medicinal Chemistry Letters 5227 (2007), WO2016044641等)と類似の方法で合成することによっても製造される。
式(4-5)で表される化合物は、例えば、下記に示される方法によって製造される。
化合物(4-3)は、化合物(4-1)と化合物(4-2)を用い、工程1-1に記載の方法に準じて製造される。化合物(4-1)は、公知の合成法(例えば、Bioorganic & Medicinal Chemistry Letters, 28, (2007), Journal of Organic Chemistry 2613, (1986)等)もしくはそれに準じた合成法によって製造されたものを用いることができる。化合物(4-2)は、市販品として又は公知の合成法(例えば、WO2012061418, WO2010097248等)もしくはそれに準じた合成法によって製造されたものを用いることができる。
化合物(4-4)は、化合物(4-3)を用い、公知の合成法(例えば、Chemical Communications 446, (2004), Journal of Organic Chemistry 8719, (2009)等)と類似の方法で環化することにより製造される。
化合物(4-5)は、化合物(4-4)を用い、保護基の脱保護を経た後に、工程1-3に記載の方法に準じて製造される。
式(5-4)で表される化合物は、例えば、下記に示される方法によって製造される。
化合物(5-2)は、化合物(1-1)と化合物(5-1)を用い、工程1-1に記載の方法に準じて製造される。化合物(5-1)は、市販品として又は公知の合成法(例えば、Journal of the American Chemical Society, 12521, (1996), Green Chemistry 451, (2005)等)もしくはそれに準じた合成法によって製造されたものを用いることができる。
化合物(5-3)は、化合物(5-2)を用い、工程1-2に記載の方法に準じて製造される。
化合物(5-4)は、化合物(5-3)を用い、工程1-3に記載の方法に準じて製造される。
また、光学異性体は前記製造法の適切な工程で、光学活性カラムを用いた方法、分別結晶化法などの公知の分離工程を実施することで分離することができる。また、出発原料として光学活性体を使用することもできる。
本明細書において、化学構造式中に立体(S、R)を表記した化合物は光学活性体を意味し、特に立体を表記していない場合にはラセミ体を意味する。本発明化合物の環状ウレア部分については、cis体、trans体が存在し、特に立体(S、R)を表記していない場合にはラセミ体を意味する。
(Boc)2O:ジ-tert-ブチルジカーボネート
Cbz:ベンジルオキシカルボニル
DIAD:アゾジカルボン酸ジイソプロピル
Boc:tert-ブトキシカルボニル
Bn:ベンジル
TBDMS:tert-ブチルジメチルシリル
Ac:アセチル
Ms:メタンスルホニル
DMSO:ジメチルスルホキシド
Ts:p-トルエンスルホニル
Tf:トリフルオロメタンスルホニル
Rt:保持時間
核磁気共鳴スペクトル(1H-NMR):
使用機器:JEOL JNM-AL400;Brucker AVANCE 400 Spectrometer
(1)Method A及びMethod B
検出機器:ACQUITY(登録商標)SQ deteceter (Waters社)
HPLC:ACQUITY UPLC(登録商標)
SYSTEM Column: Waters ACQUITY UPLC(登録商標) BEH C18(1.7um, 2.1mm × 30mm)
流速:0.8mL/min;検出UV:220nm and 254nm;温度:40℃
検出機器:ACQUITY(登録商標)QDa deteceter (Waters社)
HPLC:ACQUITY UPLC(登録商標)
SYSTEM Column: Waters ACQUITY UPLC(登録商標) BEH C18(1.7um, 2.1mm × 30mm)
流速:0.6mL/min;検出UV:20~400nm;温度:40℃
検出機器:ACQUITY(登録商標)SQ deteceter 2 (Waters社)
HPLC:ACQUITY UPLC(登録商標)
SYSTEM Column: Waters ACQUITY UPLC(登録商標) BEH C18(1.7um, 2.1mm × 50mm)
流速:0.6mL/min;検出UV:210nm~400nm;温度:35℃
検出機器:LCMS-2010A (島津製作所)
HPLC:Prominence(登録商標)
SYSTEM Column:Cadenza CD-C18(3.0um, 2.0mm × 50mm)
流速:0.5mL/min;検出UV:215、254nm;温度:40℃
参考例1:tert-ブチル cis-3-アミノ-4-{[(2,3-ジヒドロ-1-ベンゾフラン-4-イル)カルバモチオイル]アミノ}ピペリジン-1-カルボキシレート
参考例2:tert-ブチル cis-4-アミノ-3-{[(2,3-ジヒドロ-1-ベンゾフラン-4-イル)カルバモチオイル]アミノ}ピペリジン-1-カルボキシレート
参考例1:LC-MS [M+H]+/Rt (min): 393.2/0.562 (Method B)
参考例2:LC-MS [M+H]+/Rt (min): 393.2/0.559 (Method B)
tert-ブチル cis-4-アミノ-3- [(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)アミノ]ピペリジン-1-カルボキシレート
LC-MS [M+H]+/Rt (min): 391.2/0.600 (Method B)
tert-ブチル cis-3-(7,8-ジヒドロベンゾフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-カルボキシレート
LC-MS [M+H]+/Rt (min): 417.2/0.803 (Method B)
(2S,3R)-3-(ベンジルアミノ)-4-{[tert-ブチル(ジメチル)シリル]オキシ}ブタン-2-オール
LC-MS [M+H]+/Rt (min): 310.3/0.872 (Method A)
ベンジル ベンジル[(2R,3S)-1-{[tert-ブチル(ジメチル)シリル]オキシ}-3-ヒドロキシブタン-2-イル]カルバメート
LC-MS [M+H]+/Rt (min): 444.4/1.389 (Method A)
ベンジル ベンジル[(2S,3R)-1-{[tert-ブチル(ジメチル)シリル]オキシ}-3-(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)ブタン-2-イル]カルバメート
LC-MS [M+H]+/Rt (min): 573.4/1.488 (Method A).
2-[(2R,3S)-3-アミノ-4-{[tert-ブチル(ジメチル)シリル]オキシ}ブタン-2-イル]-1H-イソインドール-1,3(2H)-ジオン
LC-MS [M+H]+/Rt (min): 349.3/0.906 (Method A).
N-[(2S,3S)-1-{[tert-ブチル(ジメチル)シリル]オキシ}-3-(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)ブタン-2-イル]-N‘-(2,3-ジヒドロ-1-ベンゾフラン-7-イル)チオウレア
LC-MS [M+H]+/Rt (min): 526.3/1.251 (Method B).
2-{(2S,3S)-4-{[tert-ブチル(ジメチル)シリル]オキシ}-3-[(6,7-ジヒドロフロ[2,3-e][1,3]ベンゾチアゾール-2-イル)アミノ]ブタン-2-イル}-1H-イソインドール-1,3(2H)-ジオン
LC-MS [M+H]+/Rt (min): 524.4/1.353 (Method A).
(2S,3S)-1-{[tert-ブチル(ジメチル)シリル]オキシ}-N2-(6,7-ジヒドロフロ[2,3-e][1,3]ベンゾチアゾール-2-イル)ブタン-2,3-ジアミン
LC-MS [M+H]+/Rt (min): 394.3/0.948 (Method A).
(4S,5S)-5-({[tert-ブチル(ジメチル)シリル]オキシ}メチル)-1-(6,7-ジヒドロフロ[2,3-e][1,3]ベンゾチアゾール-2-イル)-4-メチルイミダゾリジン-2-オン
LC-MS [M+H]+/Rt (min): 420.3/1.241 (Method A).
(4S,5S)-1-(6,7-ジヒドロフロ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-(ヒドロキシメチル)-4-メチルイミダゾリジン-2-オン
LC-MS [M+H]+/Rt (min): 306.1/0.600 (Method B).
[(4S,5S)-3-(6,7-ジヒドロフロ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-メチル-2-オキソイミダゾリジン-4-イル]メチル メタンスルホネート
LC-MS [M+H]+/Rt (min): 306.1/0.600 (Method B).
tert-ブチル cis-3,4-ジアジドアゼパン-1-カルボキシレート
LC-MS [M+H]+/Rt (min): 282.2/1.045 (Method B).
tert-ブチル cis-3,4-ジアミノアゼパン-1-カルボキシレート
LC-MS [M+H]+/Rt (min): 230.2/0.276 (Method B).
5-ブロモ-4-イソチオシアネート-2H-1,3-ベンゾジオキソール
1H-NMR (DMSO-D6) δ: 7.18 (1H, d, J = 8.4 Hz), 6.91 (1H, d, J = 8.4 Hz), 6.22 (2H, s).
tert-ブチル {(3R,4R)-4-[(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)アミノ]オキサン-3-イル}カルバメート
1H-NMR (CDCl3) δ: 7.00 (1H, d, J = 8.2 Hz), 6.68 (1H, d, J = 8.2 Hz), 6.16 (1H, s), 6.07-5.99 (2H, m), 5.27 (1H, s), 4.21 (1H, d, J = 8.2 Hz), 4.05 (1H, s), 3.97 (1H, dd, J = 4.5, 11.9 Hz), 3.90-3.83 (1H, m), 3.69-3.61 (1H, m), 3.61-3.51 (1H, m), 2.38-2.25 (1H, m), 1.73 ((1H, dtd, J = 4.9, 12.0, 13.5 Hz), 1.47 (9H, s).
5-イソチオシアネート-2,3-ジヒドロ-1,4-ベンゾジオキシン
1H-NMR (CDCl3) δ: 6.80-6.67 (3H, m), 4.37-4.33 (2H, m), 4.28-4.24 (2H, m).
(3R,4S,6R)-6-シアノオキサン-3,4-ジイル ジアセテート
1H-NMR (CDCl3) δ: 5.38-5.28 (1H, m), 5.21-5.13 (1H, m), 4.84 (1H, t, J = 4.6 Hz), 4.01 (1H, dd, J = 2.5, 12.9 Hz), 3.93 (1H, dd, J = 4.5, 12.9 Hz), 2.42-2.29 (1H, m), 2.14-2.08 (4H, m), 2.07 (3H, s).
メチル 2,6-アンヒドロ-3-デオキシ-D-リボ-ヘキソナート
1H-NMR (CDCl3) δ: 4.39 (1H, ddd, J = 0.7, 3.0, 10.8 Hz), 4.19-4.10 (1H, m), 3.94-3.87 (1H, m), 3.86-3.79 (1H, m), 3.77 (3H, s), 3.66 (1H, dd, J = 9.4, 10.8 Hz), 2.41 (1H, dd, J = 1.1, 2.9 Hz), 2.28-2.18 (2H, m), 1.97-1.86 (1H, m).
メチル 2,6-アンヒドロ-4,5-O-ベンジリデン-3-デオキシ-D-リボ-ヘキソナート
1H-NMR (CDCl3) δ: 7.60-7.31 (5H, m), 6.35 (0.4H, s), 5.79 (0.6H, s), 4.58-3.98 (4H, m), 3.83-3.72 (3H, m), 3.72-3.47 (1H, m), 2.60-2.40 (1H, m), 2.15-1.96 (1H, m).
2,6-アンヒドロ-4,5-O-ベンジリデン-3-デオキシ-D-リボ-ヘキシトール
1H-NMR (CDCl3) δ: 7.59-7.31 (5H, m), 6.34 (0.4H, s), 5.83 (0.6H, s), 4.54-4.20 (2H, m), 4.11-3.92 (2H, m), 3.84-3.62 (2H, m), 2.24-1.73 (3H, m).
2,6-アンヒドロ-4,5-O-ベンジリデン-1,3-ジデオキシ-1-ヨード-D-リボ-ヘキシトール
1H-NMR (CDCl3) δ: 7.61-7.31 (5H, m), 6.34 (0.4H, s), 5.75 (0.6H, s), 4.55-4.23 (2H, m), 4.14-3.94 (1H, m), 3.73-3.47 (2H, m), 3.34-3.10 (2H, m), 2.41-2.30 (1H, m), 1.94-1.67 (1H, m).
2,6-アンヒドロ-4,5-O-ベンジリデン-1,3-ジデオキシ-1-フルオロ-D-リボ-ヘキシトール
1H-NMR (CDCl3) δ: 7.57-7.32 (5H, m), 6.38 (0.4H, s), 5.90 (0.6H, s), 4.57-4.26 (4H, m), 4.15-3.85 (2H, m), 3.63-3.49 (1H, m), 2.22-1.84 (2H, m).
2,6-アンヒドロ-4,5-O-ベンジリデン-3-デオキシ-D-リボ-ヘキソース
1H-NMR (CDCl3) δ: 9.70 (1H, s), 7.58-7.45 (2H, m), 7.43-7.37 (1H, m), 5.92 (1H, s), 4.57-4.43 (1H, s), 4.35-4.14 (2H, m), 4.01 (1H, dd, J = 5.3, 12.1 Hz), 3.64 (1H, dd, J = 7.2, 12.1 Hz), 2.44 (1H,ddd, J = 2.6, 3.8, 15.1 Hz), 1.92 (1H, ddd, J = 3.8, 11.9, 15.1 Hz).
3,7-アンヒドロ-5,6-O-ベンジリデン-1,2,4-トリデオキシ-D-リボ-ヘプト-1-イニトール
1H-NMR (CDCl3) δ: 7.57-7.46 (2H, m), 7.45-7.34 (3H, m), 5.91 (1H, s), 4.56-4.45 (2H, m), 4.27-4.23 (1H, m), 4.10 (1H, dd, J = 4.9, 12.5 Hz), 3.71 (1H, dd, J = 6.1, 12.5 Hz), 2.50 (1H, d, J = 2.2 Hz), 2.38-2.32 (1H, m), 2.20-2.13 (1H, m).
2,6-アンヒドロ-4,5-O-ベンジリデン-1,3-ジデオキシ-D-リボ-ヘキシトール
1H-NMR (CDCl3) δ: 7.60-7.32 (5H, m), 6.37 (0.4H, s), 5.78 (0.6H, s), 4.09-3.91 (1H, m), 3.82-3.64 (1H, m), 3.56-3.32 (1H, m), 2.32-2.11 (1H, m), 1.85-1.62 (1H, m), 1.24-1.14 (3H, m).
2,6-アンヒドロ-1,3-ジデオキシ-D-リボ-ヘキシトール
1H-NMR (CDCl3) δ: 4.18-4.02 (1H, m), 3.91-3.66 (3H, m), 3.64-3.44 (1H, m), 2.18 (1H, d, J = 3.1 Hz), 2.04-1.94 (1H, m), 1.90 (1H, ddd, J = 2.2, 3.8, 14.3 Hz), 1.54 (1H, dddd, J = 1.2, 2.7, 11.1, 14.1 Hz), 1.16 (3H, d, J = 6.3 Hz).
3,7-アンヒドロ-1,2,4-トリデオキシ-D-リボ-ヘプチトール
1H-NMR (CDCl3) δ: 4.16-4.07 (1H, m), 3.81-3.69 (2H, m), 3.62-3.49 (2H, m), 2.33-2.27 (1H, m), 2.16 (1H, d, J = 6.3 Hz), 1.91 (1H, ddd, J = 2.2, 3.8, 14.3 Hz), 1.59-1.34 (3H, m), 0.93 (3H, t, J = 7.5 Hz).
tert-ブチル 3-ブテン-1-イル(1-(ヒドロキシメチル)シクロプロピル)カルバメート
LC-MS [M+H]+/Rt (min): 242.5/0.936 (Method B)
tert-ブチル 3-ブテン-1-イル(1-ホルミルシクロプロピル)カルバメート
LC-MS [M-56+H]+/Rt (min): 184.3/1.029 (Method B)
tert-ブチル 3-ブテン-1-イル(1-ビニルシクロプロピル)カルバメート
LC-MS [M-56+H]+/Rt (min): 182.3/1.282 (Method B)
tert-ブチル 2-プロペン-1-イル[1-(2-プロペン-1-イル)シクロプロピル]カルバメート
1H-NMR (DMSO-d6) δ: 5.82-5.72 (2H, m), 5.21-4.80 (4H, m), 3.79 (2H, brs), 2.29 (2H, brs), 1.42 (9H, s), 0.85 (2H, brs), 0.64 (2H, brs).
tert-ブチル 4-アザスピロ[2.5]-7-オクテン-4-カルボキシレート
LC-MS [M-56+H]+/Rt (min): 154.1/1.151 (Method B)
tert-ブチル (2S)-2-メチル-4-[(トリフルオロメタンスルホニル)オキシ]-3,6-ジヒドロピリジン-1(2H)-カルボキシレート
参考例101
tert-ブチル (6S)-6-メチル-4-[(トリフルオロメタンスルホニル)オキシ]-3,6-ジヒドロピリジン-1(2H)-カルボキシレート
1H-NMR (DMSO-d6) δ: 5.73-5.69 (1H, m), 4.64-3.60 (2H, m), 2.97-2.51 (1H, m), 2.23-2.02 (1H, m), 1.46 (s, 4.5H), 1.45 (s, 4.5H), 1.21 (1.5H, d, J = 6.8 Hz), 1.16 (1.5H, d, J = 6.8 Hz).
tert-ブチル (2S)-2-メチル-3,6-ジヒドロピリジン-1(2H)-カルボキシレート
参考例105
tert-ブチル (6S)-6-メチル-3,6-ジヒドロピリジン-1(2H)-カルボキシレート
1H-NMR (DMSO-d6) δ: 5.78-5.55 (2H, m), 4.46-3.47 (2H, m), 2.80-1.78 (2H, m), 1.45 (s, 4.5H), 1.44 (s, 4.5H), 1.14 (1.5H, d, J = 6.8 Hz), 1.08 (1.5H, d, J = 6.8 Hz).
tert-ブチル rac-(3R,4R,5R)-3-{[tert-ブチル(ジメチル)シリル]オキシ}-4,5-ジヒドロキシピペリジン-1-カルボキシレート
LC-MS [M+H]+/Rt (min): 348.2/1.066 (Method B)
1,6-アンヒドロ-2,3-ジデオキシ-D-エリスロ-2-ヘキセニトール
1H-NMR (CDCl3) δ: 3.87-3.81 (1H, m), 3.79-3.71 (4H, m), 3.63-3.56 (1H, m), 1.95-1.81 (2H, m), 1.81-1.71 (1H, m), 1.72-1.56 (1H, m).
(2R,4S,5R)-2-シアノ-5-[(4-メチルベンゼン-1-スルホニル)オキシ]オキサン-4-イル 4-メチルベンゼン-1-スルホネート
1H-NMR (CDCl3) δ: 7.74 (2H, d, J = 6.4 Hz), 7.71 (2H, d, J = 6.4 Hz), 7.39-7.32(4H, m), 4.78-4.68 (2H, m), 4.51 (1H, dt, J = 2.9, 5.6 Hz), 4.01 (1H, dd, J = 5.6, 12.9 Hz), 3.80 (1H, dd, J = 2.7, 12.9 Hz), 2.49-2.42 (1H, m), 2.47 (6H, s), 2.01-1.87 (1H, m).
tert-ブチル rac-(3R,4R,5S)-3,4-ジアジド-5-ヒドロキシピペリジン-1-カルボキシレート
LC-MS [M+H]+/Rt (min): 284.2/0.829 (Method B)
tert-ブチル rac-(3R,4R,5R)-3,4-ジアジド-5-フルオロピペリジン-1-カルボキシレート
LC-MS [M+H]+/Rt (min): 286.1/0.944 (Method B)
tert-ブチル 7-オキサ-3-アザスピロ[ビシクロ[4.1.0]ヘプタン-2,1’-シクロプロパン]-3-カルボキシレート
LC-MS [M+H]+/Rt (min): 226.1/0.979 (Method B)
tert-ブチル rac-(7R,8R)-8-アジド-7-ヒドロキシ-4-アザスピロ[2.5]オクタン-4-カルボキシレート
LC-MS [M+H]+/Rt (min): 269.3/0.892 (Method A)
tert-ブチル rac-(6R,7S)-6,7-じアミノ-4-アザスピロ[2.5]オクタン-4-カルボキシレート
LC-MS [M+H]+/Rt (min): 242.2/0.241 (Method B)
ジ-tert-ブチル (3R,4R)-2,3,4,7-テトラヒドロオキセピン-3,4-ジイルビス rac-カルバメート
1H-NMR (CDCl3) δ: 5.26 (2H, s), 4.08-3.90 (1H, m), 3.89-3.71 (2H, m), 3.72-3.50 (3H, m), 1.92-1.62 (4H, m), 1.46 (9H, s), 1.45 (9H, s).
tert-ブチル rac-{(3R,4S)-4-[(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)アミノ]オキソラン-3-イル}カルバメート
LC-MS [M+H]+/Rt (min): 378.1/3.197 (Method C)
tert-ブチル rac-(3aR,6aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロ-1H-フロ[3,4-d]イミダゾール-1-カルボキシレート
LC-MS [M+H]+/Rt (min): 404.6/2.568 (Method D)
tert-ブチル (3aS,6aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロ-1H-フロ[3,4-d]イミダゾール-1-カルボキシレート
参考例272
tert-ブチル (3aR,6aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロ-1H-フロ[3,4-d]イミダゾール-1-カルボキシレート
カラム:CHIRALCEL(商標登録) OJ-H;溶媒:A液:二酸化炭素、B液:メタノール;移動相条件:A/B(%)=55/45;流速:90mL/min(分析時:3mL/min);検出UV:214nm;カラム温度:30℃
tert-ブチル {(3R,4R)-4-[(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)アミノ]-6,6-ジメチルオキサン-3-イル}カルバメート
LC-MS [M+H]+/Rt (min): 420.2/2.273 (Method C)
1,4-アンヒドロ-5-O-[tert-ブチル(ジメチル)シリル]-2,3-ビス-O-(トリフルオロメタンスルホニル)-D-リビトール
1H-NMR (CDCl3) δ: 5.47-5.36 (2H, s), 4.34-4.25 (2H, m), 4.19-4.00 (1H, m), 3.87-3.70 (2H, m), 0.90 (9H, s), 0.09 (3H, s), 0.08 (3H, s).
2,5-アンヒドロ-1-O-[tert-ブチル(ジメチル)シリル]-D-アラビニトール
1H-NMR (DMSO-d6) δ: 4.80 (1H, d, J = 6.1 Hz), 4.58 (1H, d, J = 4.6 Hz), 4.17-4.07 (1H, m), 3.97-3.90 (1H, m), 3.82-3.74 (2H, m), 3.30 (1H, dd, J = 6.7, 8.2 Hz), 3.66-3.57 (1H, m), 3.45 (1H, dd, J = 6.8, 8.2 Hz), 0.86 (9H, s), 0.03 (3H, s), 0.03 (3H, s).
参考例47に記載の方法に準じ、対応する原料化合物を用いて、参考例282および283の化合物を得た。
参考例284および285
参考例38に記載の方法に準じ、対応する原料化合物を用いて、参考例284および285の化合物を得た。
参考例286
参考例42に記載の方法に準じ、対応する原料化合物を用いて、参考例286の化合物を得た。
参考例287
参考例44に記載の方法に準じ、対応する原料化合物を用いて、参考例287の化合物を得た。
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
LC-MS [M+H]+/Rt (min): 317.1/0.399 (Method B) ; 1H-NMR (DMSO-d6) δ: 7.73 (1H, s), 7.57 (1H, d, J = 8.5 Hz), 6.72 (1H, d, J = 8.5 Hz), 4.64-4.56 (2H, m), 4.52-4.44 (1H, m), 4.04-3.99 (1H, m), 3.53-3.46 (1H, m), 3.39-3.33 (2H, m), 2.77-2.69 (1H, m), 2.62-2.51 (2H, m), 2.30-2.19 (1H, m), 1.81-1.69 (2H, m).
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
LC-MS [M+H]+/Rt (min): 331.1/0.412 (Method B); 1H-NMR (DMSO-d6) δ: 7.73 (1H, s), 7.58 (1H, d, J = 7.9 Hz), 6.73 (1H, d, J = 7.9 Hz), 4.69-4.56 (3H, m), 4.00-3.94 (1H, m), 3.43-3.27 (3H, m), 2.56-2.51 (1H, m), 2.16 (3H, s), 2.12-2.04 (1H, m), 1.96-1.75 (3H, m).
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-メトキシエチル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
LC-MS [M+H]+/Rt (min): 375.1/0.463 (Method B); 1H-NMR (CDCl3) δ: 7.45 (1H, d, J = 8.2 Hz), 6.76 (1H, d, J = 8.2 Hz), 4.92-4.85 (1H, m), 4.77 (1H, s), 4.70-4.61 (2H, m), 4.09-4.05 (1H, m), 3.69-3.63 (1H, m), 3.51-3.38 (4H, m), 3.34 (3H, s), 2.82-2.76 (1H, m), 2.65-2.54 (2H, m), 2.34-2.26 (1H, m), 2.20-2.02 (2H, m), 1.91-1.87 (1H, m).
cis-5-アセチル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
LC-MS [M+H]+/Rt (min): 359.1/0.566 (Method B); 1H-NMR (DMSO-d6, 100℃) δ: 7.59 (1H, br s), 7.54 (1H, d, J = 7.9 Hz), 6.72 (1H, d, J = 7.9 Hz), 4.83-4.78 (1H, m), 4.62 (2H, t, J = 8.8 Hz), 4.30-4.17 (2H, m), 3.85-3.78 (1H, m), 3.52-3.41 (2H, m), 3.39 (2H, t, J = 8.8 Hz), 2.13-2.02 (1H, m), 1.94-1.68 (4H, m).
(3aR,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン
LC-MS [M+H]+/Rt (min): 320.0/1.990 (Method C); 1H-NMR (DMSO-d6) δ: 7.96 (1H, s), 7.37 (1H, d, J = 8.2 Hz), 6.93 (1H, d, J = 8.2 Hz), 6.10 (2H, dd, J = 1.1, 5.0 Hz), 4.78 (1H, ddd, J = 6.1, 7.3, 8.6 Hz), 3.90-3.72 (3H, m), 3.67 (1H, dd, J = 2.7, 12.8 Hz), 3.44 (1H, ddd, J = 3.0, 10.2, 11.5), 2.46-2.28 (1H, m), 1.85-1.68 (1H, m).
(4R,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-[(ジメチルアミノ)メチル]-4-メチルイミダゾリジン-2-オン
LC-MS [M+H]+/Rt (min): 333.2/0.569 (Method A); 1H-NMR (400 MHz, CDCl3) δ: 7.45 (1H, d, J = 7.9 Hz), 6.76 (1H, d, J = 7.9 Hz), 4.93 (1H, s), 4.66 (2H, t, J = 8.9 Hz), 4.40-4.34 (1H, m), 3.90-3.84 (1H, m), 3.44 (2H, dt, J = 2.0, 8.9 Hz), 2.87 (1H, dd, J = 2.4, 11.9 Hz), 2.34 (1H, dd, J = 10.1, 11.9 Hz), 2.34 (6H, s), 1.35 (3H, d, J = 7.3 Hz).
(3aS,7aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
実施例28
(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
カラム:CHIRALPAK(商標登録) IG;溶媒:A液:クロロホルム、B液:2-プロパノール;移動相条件:A/B=9/1;流速:5mL/min;検出UV:254nm;カラム温度:40℃
cis-5-シクロプロピル-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
LC-MS [M+H]+/Rt (min): 373.3/0.585 (Method A); 1H-NMR (DMSO-d6) δ: 7.72 (1H, s), 7.27 (1H, d, J = 8.5 Hz), 6.79 (1H, d, J = 8.5 Hz), 4.61-4.53 (1H, m), 4.41-4.25 (4H, m), 3.98-3.92 (1H, m), 3.49-3.41 (1H, m), 2.75-2.67 (1H, m), 2.45-2.36 (1H, m), 2.35-2.27 (1H, m), 1.86-1.75 (2H, m), 1.68-1.63 (1H, m), 0.43-0.37 (2H, m), 0.33-0.23 (2H, m).
(3aS,7aR)-5-シクロプロピル-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
実施例34
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
カラム:CHIRALPAK(商標登録) IG;溶媒:A液:クロロホルム、B液:メタノール、C液:ジエチルアミン;移動相条件:A/B/C=99/1/0.001;流速:0.5mL/min;検出UV:280nm;カラム温度:25℃
(3aS,7aR)-5-シクロプロピル-3-(2H―[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
実施例36
(3aR,7aS)-5-シクロプロピル-3-(2H―[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
カラム:CHIRALPAK(商標登録) IG;溶媒:A液:クロロホルム、B液:メタノール、C液:ジエチルアミン;移動相条件:A/B/C=99/1/0.002;流速:5mL/min;検出UV:280nm;カラム温度:40℃
(3aS,7aR)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
実施例110
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
カラム:CHIRALPAK(商標登録) IG;溶媒:A液:クロロホルム、B液:メタノール、C液:ジエチルアミン;移動相条件:A/B/C=99/1/0.002;流速:7mL/min;検出UV:280nm;カラム温度:40℃
[(3aS,7aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-イル]アセトニトリル
実施例112
[(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-イル]アセトニトリル
カラム:CHIRALPAK(商標登録) IC;溶媒:A液:クロロホルム、B液:メタノール、C液:ジエチルアミン;移動相条件:A/B/C=98/1/0.001;流速:10mL/min;検出UV:254nm;カラム温度:40℃
(3aS,7aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
実施例114
(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン
カラム:CHIRALPAK(商標登録) IC;溶媒:A液:クロロホルム、B液:メタノール、C液:ジエチルアミン;移動相条件:A/B/C=99/1/0.001;流速:10mL/min;検出UV:254nm;カラム温度:40℃
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-ヒドロキシヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン
LC-MS [M+H]+/Rt (min): 334.1/2.761 (Method C); 1H-NMR (DMSO-d6) δ: 7.95 (1H, s), 7.59 (1H, d, J = 8.4 Hz), 6.74 (1H, d, J = 8.4 Hz), 6.40 (1H, d, J = 4.9 Hz), 5.00-4.85 (1H, m), 4.81 (1H, td, J = 4.4, 9.1 Hz), 4.67-4.52 (2H, m), 3.98-3.84 (2H, m), 3.49-3.43 (1H, m), 3.42-3.34 (1H, m), 2.77-2.68 (1H, m), 2.00-1.90 (2H, m).
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-フルオロヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン
LC-MS [M+H]+/Rt (min): 336.1/2.123 (Method C); 1H-NMR (DMSO-d6) δ: 8.08 (1H, s), 7.60 (1H, d, J = 8.4 Hz), 6.75 (1H, d, J = 8.4 Hz), 5.67 (1H, ddd, J = 5.0, 6.9, 60.9 Hz), 4.94-4.83 (1H, m), 4.67-4.54 (2H, m), 4.13-3.96 (2H, m), 3.68 (1H, d, J = 12.6 Hz), 3.45-3.33 (2H, m), 3.22-3.02 (1H, m), 2.32-2.14 (1H, m).
(3aR,6R,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メチルテトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン
LC-MS [M+H]+/Rt (min): 318.1/2.123 (Method C); 1H-NMR (DMSO-d6) δ: 8.17 (1H, s), 7.60 (1H, d, J = 8.4 Hz), 6.75 (1H, d, J = 8.4 Hz), 4.68 (1H, dd, J = 2.4, 8.7 Hz), 4.65-4.58 (2H, m), 4.46-4.38 (1H, m), 4.29-4.21 (1H, m), 4.02-3.94 (1H, m), 3.65 (1H, dd, J = 2.6, 9.9 Hz), 3.50-3.38 (2H, m), 1.38 (3H, d, J = 6.6 Hz).
[(3aS,4R,6aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロ-1H-フロ[3,4-d]イミダゾール-4-イル]アセトニトリル
LC-MS [M+H]+/Rt (min): 343.1/2.090 (Method C); 1H-NMR (DMSO-d6) δ: 8.27 (1H, s), 7.61 (1H, d, J = 8.4 Hz), 6.76 (1H, d, J = 8.4 Hz), 4.82 (1H, dd, J = 3.1, 8.9 Hz), 4.69-4.56 (2H, m), 4.49-4.56 (2H, m), 4.49-4.41 (1H, m), 4.37 (1H, dt, J = 3.1, 6.2 Hz), 4.13 (1H, dd, J = 5.2, 9.9 Hz), 3.72 (1H, dd, J = 3.3, 10.0 Hz 3.45-3.36 (2H, m), 3.19-3.17 (2H, m).
試験例1
(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。
「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。
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。
(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。
この結果は、被験化合物(本発明化合物(1))が、強いDYRK阻害活性を有することを示している。
試験例2
本試験では、8~12週齢のマウス(B6C3F1、雌性、日本チャールス・リバー)を用いた。0.5%メチルセルロース溶液あるいは0.5%メチルセルロース溶液に懸濁させた実施例化合物をマウスへ10mL/kgで単回あるいは反復経口投与し、最終投与翌日以降に、イソフルラン麻酔下で後大静脈より採血した血液をEDTA-2K入り採血管で抗凝固処理し、網赤血球数を多項目自動血球分析装置(Sysmex社製)で定量した。
[評価結果]
本発明化合物が薬効領域において安全性を示すことを確認した。
Claims (21)
- 下記式(1):
A1は、酸素原子又は窒素原子(=N-)を表し、
A2は、CRB、CRCRD、酸素原子又はNRA1を表し、
L1は、置換されていてもよいメチレン、置換されていてもよいエチレン、置換されていてもよいメチン、置換されていてもよいエタンジイリデン、=N-又はNRA2を表し、
RA1、RA2、RB、RCおよびRDは、それぞれ独立して、水素原子又は置換されていてもよいC1-6アルキルを表し、
R1は、水素原子、ハロゲン原子又は置換されていてもよいC1-6アルキルを表し、
Xは、炭素原子又は窒素原子を表し、
L2は、置換されていてもよいC1-4アルキレンを表し、
REは、置換されていてもよいC1-6アルキルを表し、
Zは、-NR2R3又は-OR7を表し、
R7は、置換されていてもよいC1-6アルキル、又はR4とともに形成される、置換されていてもよいC1-7アルキレンを表し、ここにおいて、R4およびR7が、それぞれが結合する炭素原子および酸素原子と一緒になって、置換されていてもよい5-11員の飽和複素環を形成し、
R2は、水素原子、置換されていてもよいC1-6アルキル、C(O)-RE、C3-10シクロアルキル、C2-6アルキニル又は4-11員の飽和複素環の環状基を表し、
R3は、水素原子、置換されていてもよいC1-6アルキル又はC(O)-REを表し、
R4は、置換されていてもよいC1-6アルキルを表し、
ここにおいて、R2およびR3が、これらが結合する窒素原子と一緒になって、置換されていてもよい4-11員の飽和複素環を形成していてもよく、あるいは、R3およびR4が、それぞれが結合する窒素原子および炭素原子と一緒になって、置換されていてもよい4-11員の飽和複素環を形成していてもよく、若しくは、前記R2、R3および窒素原子で構成される飽和複素環上の任意の炭素原子およびR4が一緒になって、4-11員の飽和複素環を形成していてもよい。]で表される化合物又はその薬学的に許容される塩。 - Zが、-NR2R3を表し、R2およびR3が、それぞれ独立して、水素原子、置換されていてもよいC1-6アルキル又はC(O)-REを表し、ここにおいて、R2およびR3が、これらが結合する窒素原子と一緒になって、置換されていてもよい4-8員の飽和複素環を形成していてもよい、請求項1に記載の化合物又はその薬学的に許容される塩。
- Zが、-NR2R3を表し、R3およびR4が、それぞれが結合する窒素原子および炭素原子と一緒になって、置換されていてもよい4-8員の飽和複素環を形成する、請求項1に記載の化合物又はその薬学的に許容される塩。
- R1が、水素原子である、請求項1-3のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- X1が、炭素原子である、請求項1-4のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- A1が、酸素原子であり、A2がメチレンであり、L1がメチレンである、請求項5に記載の化合物又はその薬学的に許容される塩。
- 式(1)が、下記式(1a):
A2は、置換されていてもよいメチレン又は酸素原子を表し、
L1は、置換されていてもよいメチレン又は置換されていてもよいエチレンを表し、
L2は、置換されていてもよいC1-4アルキレンを表し、
R2およびR3は、それぞれ独立して、水素原子、置換されていてもよいC1-6アルキル又はC(O)-REを表し、ここにおいて、R2およびR3が、これらが結合する窒素原子と一緒になって、置換されていてもよい4-8員の飽和複素環を形成していてもよく、
REは、置換されていてもよいC1-6アルキルを表し、
R4は、置換されていてもよいC1-6アルキルである。]で表される請求項1、2、4、5又は6に記載の化合物又はその薬学的に許容される塩。 - R2およびR3が、それぞれ独立して、置換されていてもよいC1-6アルキルである、請求項7に記載の化合物又はその薬学的に許容される塩。
- R2およびR3が、これらが結合する窒素原子と一緒になって、置換されていてもよい4-8員の飽和複素環を形成する、請求項7に記載の化合物又はその薬学的に許容される塩。
- L2が、C1-3アルキレンである、請求項7-9のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- 式(1)が、下記式(1b):
A2は、置換されていてもよいメチレン又は酸素原子を表し、
L1は、置換されていてもよいメチレン又は置換されていてもよいエチレンを表し、
lおよびmは、それぞれ独立して、1、2又は3を表し、ここにおいて、lとmの合計が5以下であり、
nは、1、2、3又は4を表し、
R2は、水素原子、置換されていてもよいC1-6アルキル、C3-10シクロアルキル又はC(O)-REを表し、
REは、置換されていてもよいC1-6アルキルを表し、
RFは、水素原子、ハロゲン原子又は置換されていてもよいC1-6アルキルを表し、
nが2、3又は4の場合、RFは同一でも異なっていてもよく、また同一炭素原子上の2個のRFが、それぞれ結合する炭素原子と一緒になって4-8員の飽和複素環又は3-8員の飽和炭素環からなるスピロ環を形成していてもよく、あるいは異なる炭素原子上の2個のRFが、結合して架橋を形成していてもよい。]で表される請求項1、3、4、5又は6に記載の化合物又はその薬学的に許容される塩。 - R2が、水素原子、置換されていてもよいC1-6アルキル又はC3-10シクロアルキルである、請求項11に記載の化合物又はその薬学的に許容される塩。
- R2が、置換されていてもよいC1-6アルキルである、請求項11に記載の化合物又はその薬学的に許容される塩。
- lおよびmが、それぞれ独立して、1又は2である、請求項11-13のいずれか一項に記載の化合物又はその薬学的に許容される塩。
- Zが-OR7であって、R4およびR7が、それぞれが結合する炭素原子および酸素原子と一緒になって、置換されていてもよい5-8員の飽和複素環を形成する、請求項1に記載の化合物又はその薬学的に許容される塩。
- 式(1)が、下記式(1c):
A2は、置換されていてもよいメチレン又は酸素原子を表し、
L1は、置換されていてもよいメチレン又は置換されていてもよいエチレンを表し、
pおよびqは、それぞれ独立して、1、2又は3を表し、ここにおいて、pとqの合計が5以下であり、
tは、1、2、3又は4を表し、
RGは、水素原子、ハロゲン原子、置換されていてもよいC1-6アルキル、置換されていてもよいC1-6アルコキシ又はCN基を表し、
tが2、3又は4の場合、RGは同一でも異なっていてもよく、また同一炭素原子上の2個のRGが、それぞれ結合する炭素原子と一緒になって4-8員の飽和複素環又は3-8員の飽和炭素環からなるスピロ環を形成していてもよく、あるいは異なる炭素原子上の2個のRGが、結合して架橋を形成していてもよい。]で表される請求項1又は15に記載の化合物又はその薬学的に許容される塩。 - 以下の化合物の群から選択される、請求項1-16のいずれか一項に記載の化合物又はその薬学的に許容される塩:
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例7);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-メトキシエチル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例8);
cis-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例9);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-エチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例11);
cis-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルヘキサヒドロピロロ[3,4-d]イミダゾールl-2(1H)-オン(実施例14);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(プロパン-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例15);
cis-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例17);
(3aS,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例19);
(3aR,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例21);
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチル-5-[(モルホリン-4-イル)メチル]イミダゾリジン-2-オン(実施例23);
(4R,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチル-5-[(モルホリン-4-イル)メチル]イミダゾリジン-2-オン(実施例24);
(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例28);
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例34);
(3aR,7aS)-5-シクロプロピル-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例36);
(3aR,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例37);
(3aR,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メチルヘキサヒドロピラノ[3,4ーd]イミダゾール-2(3H)-オン(実施例38);
(3aR,6S,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-メチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例39);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例40);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例41);
(3aR,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例42);
(3aR,6S,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例43);
(4S,5S)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(メトキシメチル)-4-メチルイミダゾリジン-2-オン(実施例44);
(3aR,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)テトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例65);
rac-(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例71);
rac-(3aR,7aS)-5-シクロブチル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例72);
rac-(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例73);
rac-(3aR,7aS)-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例76);
rac-(3aR,7aS)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例77);
rac-(3aR,7aS)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例78);
rac-(3aR,7aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-メチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例79);
rac-(3aR,7aS)-3-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例80);
rac-(3aR,7aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-(オキセタン-3-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例81);
rac-(3aR,8aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-メチルオクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例85);
rac-(3aR,8aS)-3-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-5-(オキセタン-3-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例86);
(3aS,6S,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5,6-ジメチルオクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例93);
rac-(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例98);
rac-(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例99);
rac-[(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-イル]アセトニトリル(実施例100);
rac-(3aR,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)ヘキサヒドロピロロ[3,4-d]イミダゾール-2(1H)-オン(実施例102);
rac-[(3aR,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロピロロ[3,4-d]イミダゾール-5(1H)-イル]アセトニトリル(実施例103);
rac-(3aR,8aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例104);
rac-(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロイミダゾ[4,5-c]アゼピン-2(1H)-オン(実施例105);
rac-[(3aR,8aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロイミダゾ[4,5-c]アゼピン-5(1H)-イル]アセトニトリル(実施例106);
rac-(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2,2,2-トリフルオロエチル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例107);
rac-(3aR,7aS)-5-(2,2-ジフルオロエチル)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例108);
(3aR,7aS)-5-シクロプロピル-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例110);
[(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロ-5H-イミダゾ[4,5-c]ピリジン-5-イル]アセトニトリル(実施例112);
(3aR,7aS)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-(2-プロピン-1-イル)オクタヒドロ-2H-イミダゾ[4,5-c]ピリジン-2-オン(実施例114);
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-{[(3S)-3-フルオロピロリジン-1-イル]メチル}-4-メチルイミダゾリジン-2-オン(実施例115);
(4S,5R)-5-[(3,3-ジフルオロアゼチジン-1-イル)メチル]-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチルイミダゾリジン-2-オン(実施例116);
(4S,5R)-5-[(3,3-ジフルオロピロリジン-1-イル)メチル]-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-4-メチルイミダゾリジン-2-オン(実施例117);
(4S,5R)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-5-[(3-フルオロアゼチジン-1-イル)メチル]-4-メチルイミダゾリジン-2-オン(実施例118);
rac-(3aR,7aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例120);
rac-(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例121);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例122);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6,6-ジメチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例124);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例127);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メトキシヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例129);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例131);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-2-オキソオクタヒドロピラノ[3,4-d]イミダゾール-6-カルボニトリル(実施例133);
(3aR,8aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)ヘキサヒドロ-1H-オキセピノ[3,4-d]イミダゾール-2(3H)-オン(実施例135);
(3aR,6S,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-6-エチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例138);
(3aR,6S,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル]-6-メチルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例139);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル]-6-(フルオロメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例140);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(ヒドロキシメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例144);
(3aR,6R,7aR)-1-(7,8-ジヒドロ[1,4]ジオキシノ[2,3-e][1,3]ベンゾチアゾール-2-イル)-6-(ヒドロキシメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例146);
(3aR,6R,7aR)-1-(2H-[1,3]ジオキソロ[4,5-e][1,3]ベンゾチアゾール-7-イル)-6-(ヒドロキシメチル)ヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例147);
(3aR,6R,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-エチニルヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例149);
(3aR,7aR)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-フルオロヘキサヒドロピラノ[3,4-d]イミダゾール-2(3H)-オン(実施例151);
(3aR,6S,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(ヒドロキシメチル)テトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例157);
(3aR,6S,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-(フルオロメチル)テトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例159);
(3aR,6R,6aS)-1-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-6-メチルテトラヒドロ-1H-フロ[3,4-d]イミダゾール-2(3H)-オン(実施例161);および
[(3aS,4R,6aR)-3-(7,8-ジヒドロフロ[3,2-e][1,3]ベンゾチアゾール-2-イル)-2-オキソヘキサヒドロ-1H-フロ[3,4-d]イミダゾール-4-イル]アセトニトリル(実施例162)。 - 請求項1-17のいずれか一項に記載の化合物又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。
- 請求項1-17のいずれか一項に記載の化合物又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。
- 請求項1-17のいずれか一項に記載の化合物又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。
- 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、慢性腎疾患又は骨吸収疾患である、請求項20に記載の治療剤及び/又は予防剤。
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