JP5683489B2 - ピペリジン含有化合物およびその用途 - Google Patents
ピペリジン含有化合物およびその用途 Download PDFInfo
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- JP5683489B2 JP5683489B2 JP2011545415A JP2011545415A JP5683489B2 JP 5683489 B2 JP5683489 B2 JP 5683489B2 JP 2011545415 A JP2011545415 A JP 2011545415A JP 2011545415 A JP2011545415 A JP 2011545415A JP 5683489 B2 JP5683489 B2 JP 5683489B2
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- substituent
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- formula
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- 150000001875 compounds Chemical class 0.000 title claims description 490
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title description 32
- 239000003814 drug Substances 0.000 claims description 92
- 229910052739 hydrogen Inorganic materials 0.000 claims description 79
- 239000001257 hydrogen Substances 0.000 claims description 79
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 64
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 30
- 229940124597 therapeutic agent Drugs 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 239000012453 solvate Substances 0.000 claims description 19
- 150000001204 N-oxides Chemical class 0.000 claims description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- UVJWSWGVXVPKQH-UHFFFAOYSA-N 4-amino-5-chloro-6-ethoxy-n-[[1-[(3-phenyl-1,2-oxazol-5-yl)methyl]piperidin-4-yl]methyl]pyridine-2-carboxamide Chemical compound NC1=C(Cl)C(OCC)=NC(C(=O)NCC2CCN(CC=3ON=C(C=3)C=3C=CC=CC=3)CC2)=C1 UVJWSWGVXVPKQH-UHFFFAOYSA-N 0.000 claims description 6
- 206010022491 Insulin resistant diabetes Diseases 0.000 claims description 6
- GIJKQTOCFGRFIV-UHFFFAOYSA-N 4-amino-5-cyano-6-ethoxy-n-[[1-[(3-phenyl-1,2-oxazol-5-yl)methyl]piperidin-4-yl]methyl]pyridine-2-carboxamide Chemical compound NC1=C(C#N)C(OCC)=NC(C(=O)NCC2CCN(CC=3ON=C(C=3)C=3C=CC=CC=3)CC2)=C1 GIJKQTOCFGRFIV-UHFFFAOYSA-N 0.000 claims description 5
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 230000000069 prophylactic effect Effects 0.000 claims description 4
- 241000023320 Luma <angiosperm> Species 0.000 claims 2
- 125000003943 azolyl group Chemical group 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 claims 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 description 516
- -1 methoxy, phenoxy Chemical group 0.000 description 285
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
- 238000006243 chemical reaction Methods 0.000 description 105
- 125000004122 cyclic group Chemical group 0.000 description 104
- 238000005481 NMR spectroscopy Methods 0.000 description 94
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 91
- 238000000034 method Methods 0.000 description 79
- 125000002950 monocyclic group Chemical group 0.000 description 78
- 229940079593 drug Drugs 0.000 description 71
- 125000002619 bicyclic group Chemical group 0.000 description 69
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 66
- 125000000217 alkyl group Chemical group 0.000 description 65
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 63
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 61
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 53
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 50
- 125000001620 monocyclic carbocycle group Chemical group 0.000 description 50
- 239000000243 solution Substances 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 46
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 46
- 230000000704 physical effect Effects 0.000 description 46
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 125000004433 nitrogen atom Chemical group N* 0.000 description 44
- 125000005842 heteroatom Chemical group 0.000 description 43
- 125000004430 oxygen atom Chemical group O* 0.000 description 42
- 125000004434 sulfur atom Chemical group 0.000 description 42
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 41
- 229920006395 saturated elastomer Polymers 0.000 description 41
- 125000006239 protecting group Chemical group 0.000 description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 37
- 125000000623 heterocyclic group Chemical group 0.000 description 37
- 238000002360 preparation method Methods 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 33
- 235000002639 sodium chloride Nutrition 0.000 description 33
- 150000002431 hydrogen Chemical class 0.000 description 32
- 239000012044 organic layer Substances 0.000 description 31
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 30
- 238000010511 deprotection reaction Methods 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 25
- 125000000547 substituted alkyl group Chemical group 0.000 description 25
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- TXIFKGWOQSVIMZ-UHFFFAOYSA-N 4-phenylthiophene-2-carbaldehyde Chemical compound S1C(C=O)=CC(C=2C=CC=CC=2)=C1 TXIFKGWOQSVIMZ-UHFFFAOYSA-N 0.000 description 22
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 22
- 238000004440 column chromatography Methods 0.000 description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 20
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 20
- 125000002947 alkylene group Chemical group 0.000 description 20
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 19
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 19
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 18
- 125000002837 carbocyclic group Chemical group 0.000 description 18
- 208000026106 cerebrovascular disease Diseases 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 17
- 239000007924 injection Substances 0.000 description 17
- 238000002347 injection Methods 0.000 description 17
- 238000004519 manufacturing process Methods 0.000 description 17
- 125000003277 amino group Chemical group 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 239000003960 organic solvent Substances 0.000 description 16
- 125000005750 substituted cyclic group Chemical group 0.000 description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 15
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- 150000001299 aldehydes Chemical class 0.000 description 14
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 14
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 14
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 14
- 238000006268 reductive amination reaction Methods 0.000 description 14
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 13
- 239000002253 acid Substances 0.000 description 13
- 125000004450 alkenylene group Chemical group 0.000 description 13
- 238000007112 amidation reaction Methods 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 12
- OXUUNDMDOOXPKY-UHFFFAOYSA-N 4-chloro-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1Cl OXUUNDMDOOXPKY-UHFFFAOYSA-N 0.000 description 12
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 12
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 12
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 12
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 206010012601 diabetes mellitus Diseases 0.000 description 11
- 235000010355 mannitol Nutrition 0.000 description 11
- 230000003449 preventive effect Effects 0.000 description 11
- 230000001225 therapeutic effect Effects 0.000 description 11
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 10
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 10
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 10
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 10
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 10
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 10
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 10
- 150000002244 furazanes Chemical class 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 10
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 229930192474 thiophene Natural products 0.000 description 10
- 150000003852 triazoles Chemical class 0.000 description 10
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 9
- DTHHUAXKOMWYBI-UHFFFAOYSA-N oxadiazolidine Chemical compound C1CONN1 DTHHUAXKOMWYBI-UHFFFAOYSA-N 0.000 description 9
- 239000000825 pharmaceutical preparation Substances 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 235000019698 starch Nutrition 0.000 description 9
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 8
- GJLOKYIYZIOIPN-UHFFFAOYSA-N 5-chloropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)C=N1 GJLOKYIYZIOIPN-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 8
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
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- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 125000000169 tricyclic heterocycle group Chemical group 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WIOADUFWOUUQCV-UHFFFAOYSA-N triphenylphosphanium dichloride Chemical compound [Cl-].[Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 WIOADUFWOUUQCV-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229940126158 β3 adrenergic receptor agonist Drugs 0.000 description 1
Classifications
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D471/04—Ortho-condensed systems
Description
新規な式(I−1)の化合物:
R3kは、ハロゲン等を表わし;R5kは、アルコキシ等を表わす;)は、c−jun N−末端キナーゼ阻害剤として糖尿病治療剤および脳梗塞治療剤として有用であることが記載されている(特許文献1参照)。
(1)式(I−1)の化合物:
Cyc21は、置換基を有していてもよい5員の単環ヘテロ環であり;
Cyc41は、置換基を有していてもよい5−10員の単環または二環の炭素環、または置換基を有していてもよい5−10員の単環または二環のヘテロ環であり;
X1は、−CH2−、−CO−または−SO2−であり;
Z1は、−N(R51)−CO−、−CO−N(R51)−、−N(R51)−、結合手または−O−であり、
基中、R51は、水素または置換基を有していてもよいC1−4のアルキル、
またはR51とCyc41の置換基が一緒になって、置換基を有していてもよいC1−4のアルキレンまたは置換基を有していてもよいC2−4のアルケニレンを形成してもよく;
R10は、水素または置換基であり;
R110は、置換基であり;
pは、0から8の整数であり、
基中、pが、2から8の整数であるとき、R110はそれぞれ同じでも異なっていてもよく;および
式中、式(I−1)の該化合物は、式(I−2)の化合物:
基中、矢印は、イソオキサゾリルの炭素との結合位置を表わし;
Cyc42は、
基中、矢印は、カルボニルの炭素との結合位置を表わし;
R6は、水素、アセチル、tert−ブトキシカルボニル、メチルスルホニルまたはフェニルスルホニルであり;
R7は、水素、塩素、フェニル、トリフルオロメチル、メトキシ、フェノキシ、シアノまたはN−アセチルアミノであり;
R8は、水素、N,N−ジメチルアミノまたはN−モルホリニルであり;および
R9は、水素、メチルまたはフェニルである。)ではない。)、その塩、そのN−オキシド、その溶媒和物またはそのプロドラッグ、
(2)
Cyc8は、(1)置換基を有していてもよい5−6員の単環炭素環または置換基を有していてもよい5−6員の単環ヘテロ環、または(2)置換基を有していてもよい8−10員の二環の炭素環または置換基を有していてもよい8−10員の二環のヘテロ環であり;
Cyc9は、(1)置換基を有していてもよい5−6員の単環炭素環または置換基を有していてもよい5−6員の単環ヘテロ環、または(2)置換基を有していてもよい8−10員の二環の炭素環または置換基を有していてもよい8−10員の二環のヘテロ環であり;
Cyc10は、置換基を有していてもよい5−6員の単環ヘテロ環であり;
Cyc11は、置換基を有していてもよい6員の単環炭素環または置換基を有していてもよい6員の単環ヘテロ環であり;
Cyc12は、置換基を有していてもよい5−10員の単環または二環の炭素環、または置換基を有していてもよい5−10員の単環または二環のヘテロ環であり;
Eは、−O− または−N(R54)−であり;
基中、R54は、水素または置換基を有していてもよいC1−4のアルキルであり;
R52は、水素または置換基を有していてもよいC1−4のアルキルであり;
R53は、水素または置換基を有していてもよいC1−4のアルキルであり;および
式中、式(I−1)の該化合物は、前記(1)記載の式(I−2)の化合物ではない;および、その他の記号は前記(1)で記載されたものと同じ意味を持つ。)前記(1)記載の化合物、
(3)Cyc8が、(1)少なくとも2つの置換基を有する5−6員の単環炭素環または少なくとも2つの置換基を有する6員の単環ヘテロ環、または(2)置換基を有していてもよい8−10員の二環の炭素環または置換基を有していてもよい8−10員の二環のヘテロ環であり;
Cyc9が、(1)少なくとも2つの置換基を有する5−6員の単環炭素環または少なくとも2つの置換基を有する5−6員の単環ヘテロ環、または(2)置換基を有していてもよい8−10員の二環の炭素環または置換基を有していてもよい8−10員の二環のヘテロ環である(基中、式(I−1)の該化合物は、前記(1)で記載された式(I−2)の化合物ではない。)前記(2)記載の化合物、
(4)Cyc8が、(1)(a)置換基を有していてもよい、イミダゾリル、トリアゾリル、ピラゾリル、フラニル、オキサゾリル、チアゾリル、イソチアゾリル、フラザニル、オキサジアゾリルまたはチアジアゾリル、または(2)(b)置換基を有する、ピロリルまたはチエニルである、前記(2)記載の化合物、
(5)式(I−1)の化合物が、式(I−1−1)の化合物:
W3およびW4は、それぞれ独立してCHまたはNであり;
R11は、ハロゲン、ヒドロキシ、置換基を有していてもよいC1−4のアルコキシ、置換基を有していてもよいC1−4のアルキル、シアノまたはアミノであり、およびR11は、それぞれ同じでも異なっていてもよく;
R12は、ハロゲン、ヒドロキシ、置換基を有していてもよいC1−4のアルコキシ、置換基を有していてもよいC1−4のアルキル、シアノまたはアミノであり;
R13は、置換基を有していてもよいC1−4のアルキルであり;
nは、2から4の整数であり;
mは、0から4の整数であり、
基中、mが、2から4の整数であるとき、R12はそれぞれ同じでも異なっていてもよく;および、その他の記号は前記(1)で記載されたものと同じ意味を持つ。)である前記(1)記載の化合物、
(6)式(I−1−5)の化合物:
Cyc21は、置換基を有していてもよい5員の単環ヘテロ環であり;
X1は、−CH2−、−CO−または−SO2−であり;
R10は、水素または置換基であり;
W5は、CHまたはNであり;
R14は、シアノまたはアミノであり;
R15は、ハロゲン、シアノまたはアミノであり;および
R16は、ハロゲン、ヒドロキシ、置換基を有していてもよいC1−4のアルコキシ、置換基を有していてもよいC1−4のアルキル、シアノまたはアミノである。)、その塩、そのN−オキシド、その溶媒和物またはそのプロドラッグ、
(7)Cyc11が、置換基を有していてもよい、ピロリジニル、フェニル、N−モルホリニルまたはピリジルであり;および
Cyc21が、置換基を有していてもよい、チアゾリル、イソオキサゾリル、チエニルまたはオキサジアゾリルである前記(5)または前記(6)記載の化合物、
(8)
(9)
X1は、−CH2−であり;
R10は、水素であり;および
R16は、クロル、ヒドロキシ、置換基を有していてもよい、メトキシまたはエトキシ、置換基を有していてもよい、メチルまたはエチル、シアノまたはアミノ;および
その他の記号は前記(5)または前記(6)で記載されたものと同じ意味を持つ。)前記(5)または前記(6)記載の化合物、
(10)化合物が、
(1)4−アミノ−5−クロロ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド、
(2)4−アミノ−5−シアノ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド、
(3)4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド、および
(4)4−アミノ−5−シアノ−N−((1−((4−((ジメチルアミノ)メチル)−2−フェニルチアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミドからなる群から選ばれる前記(6)記載の化合物、
(11)前記(6)記載の式(I−1−5)の化合物、その塩、そのN−オキシド、その溶媒和物またはそのプロドラッグを含有する医薬組成物、
(12)式(I)の化合物:
Cyc2は、置換基を有していてもよい環状基であり;
Cyc3は、置換基を有していてもよい環状基であり;
Cyc4は、置換基を有していてもよい環状基であり;
Xは、−CR3R4−、−CO−または−SO2−であり、
基中、R3およびR4は、それぞれ独立して水素または置換基を有していてもよいC1−4のアルキルであり;
R1およびR2は、それぞれ独立して水素または置換基を有していてもよいC1−4のアルキルであり;および
Zは、−N(R5)−CO−、−CO−N(R5)−、−N(R5)−、結合手または−O−であり、
基中、R5は、水素または置換基を有していてもよいC1−4のアルキルであり、またはR5とCyc4の置換基が一緒になって、置換基を有していてもよいC1−4のアルキレンまたは置換基を有していてもよいC2−4のアルケニレンを形成してもよい。)、その塩、そのN−オキシド、その溶媒和物またはそのプロドラッグの有効量を哺乳動物に対して投与することを特徴とするインシュリン抵抗性糖尿病の予防および/または治療方法、
(13)R1およびR2が、それぞれ水素であり;
Cyc1が、置換基を有していてもよい5−7員の単環炭素環または置換基を有していてもよい5−7員の単環ヘテロ環であり;
Cyc2が、置換基を有していてもよい5−7員の単環炭素環または置換基を有していてもよい5−7員の単環ヘテロ環であり;
Cyc3が、置換基を有していてもよい5−6員の単環ヘテロ環であり;および
Cyc4が、置換基を有していてもよい5−10員の単環または二環の炭素環または置換基を有していてもよい5−10員の単環または二環のヘテロ環である前記(12)記載の方法、
(14)式(I)の該化合物が、式(I−1−5)の化合物:
Cyc21は、置換基を有していてもよい5員の単環ヘテロ環であり;
X1は、−CH2−、−CO−または−SO2−であり;
R10は、水素または置換基であり;
W5は、CHまたはNであり;
R14は、シアノまたはアミノであり;
R15は、ハロゲン、シアノまたはアミノであり;および
R16は、ハロゲン、ヒドロキシ、置換基を有していてもよいC1−4のアルコキシ、置換基を有していてもよいC1−4のアルキル、シアノまたはアミノである。)である前記(13)記載の方法、
(15)インシュリン抵抗性糖尿病の予防および/または治療剤の製造のための前記(12)記載の式(I)の化合物、その塩、そのN−オキシド、その溶媒和物またはそのプロドラッグの使用、
(16)式(I)の化合物:
Cyc2は、置換基を有していてもよい環状基であり;
Cyc3は、置換基を有していてもよい環状基であり;
Cyc4は、置換基を有していてもよい環状基であり;
Xは、−CR3R4−、−CO−または−SO2−であり、
基中、R3およびR4は、それぞれ独立して水素または置換基を有していてもよいC1−4のアルキルであり;
R1およびR2は、それぞれ独立して水素または置換基を有していてもよいC1−4のアルキルであり;および
Zは、−N(R5)−CO−、−CO−N(R5)−、−N(R5)−、結合手または−O−であり、
基中、R5は、水素または置換基を有していてもよいC1−4のアルキルであり、またはR5とCyc4の置換基が一緒になって、置換基を有していてもよいC1−4のアルキレンまたは置換基を有していてもよいC2−4のアルケニレンを形成してもよい。)、その塩、そのN−オキシド、その溶媒和物またはそのプロドラッグの有効量を哺乳動物に対して投与することを特徴とする脳卒中の予防および/または治療方法、
(17)R1およびR2が、それぞれ水素であり;
Cyc1が、置換基を有していてもよい5−7員の単環炭素環または置換基を有していてもよい5−7員の単環ヘテロ環であり;
Cyc2が、置換基を有していてもよい5−7員の単環炭素環または置換基を有していてもよい5−7員の単環ヘテロ環であり;
Cyc3が、置換基を有していてもよい5−6員の単環ヘテロ環であり;および
Cyc4が、置換基を有していてもよい5−10員の単環または二環の炭素環または置換基を有していてもよい5−10員の単環または二環のヘテロ環である前記(16)記載の方法、
(18)式(I)の該化合物が、式(I−1−5)の化合物:
Cyc21は、置換基を有していてもよい5員の単環ヘテロ環であり;
X1は、−CH2−、−CO−または−SO2−であり;
R10は、水素または置換基であり;
W5は、CHまたはNであり;
R14は、シアノまたはアミノであり;
R15は、ハロゲン、シアノまたはアミノであり;および
R16は、ハロゲン、ヒドロキシ、置換基を有していてもよいC1−4のアルコキシ、置換基を有していてもよいC1−4のアルキル、シアノまたはアミノである。)である前記(17)記載の方法、および
(19)脳卒中の予防および/または治療剤の製造のための前記(16)記載の式(I)の化合物、その塩、そのN−オキシド、その溶媒和物またはそのプロドラッグの使用に関する。
直鎖状または分枝状のC1−10アルキル基(例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、ペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル基等)、直鎖状または分枝状のC2−6アルケニル基(例えば、エテニル、プロペニル、ブテニル、ブタジエニル、ペンテニル、ペンタジエニル、ヘキセニル、ヘキサジエニル基等)、直鎖状または分枝状のC2−6アルキニル基(例えば、エチニル、プロピニル、ブチニル、ブタジイニル、ペンチニル、ペンタジイニル、ヘキシニル、ヘキサジイニル基等)、水酸基、C1−4アルコキシ基(例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec−ブトキシ、tert−ブトキシ基等)、C6−10アリルオキシ(例えば、フェノキシ、ベンジルオキシ等)、チオール、C1−6アルキルチオ基(例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、イソブチルチオ、tert−ブチルチオ、ペンチルチオ、ヘキシルチオ基等)、C6−10アリールチオ基(例えば、フェニルチオ基等)、アミノ基、モノ−またはジ−(C1−6アルキル)アミノ基(例えば、メチルアミノ、エチルアミノ、プロピルアミノ、ジメチルアミノ、ジエチルアミノ基等)、モノ−またはジ−(C6−10アリール)アミノ基(例えば、フェニルアミノ、ジフェニルアミノ基等)、モノ−(C1−6アルキル)−モノ−(C6−10アリール)アミノ基(例えば、N−フェニル−N−メチルアミノ、N−フェニル−N−エチルアミノ基等)、モノ−またはジ−(C1−6アルキル)アミノアルコキシ(例えば、メチルアミノエトキシ、エチルアミノエトキシ、プロピルアミノエトキシ、ジメチルアミノエトキシ、ジエチルアミノエトキシ基等)、ヘテロ環アルコキシ(例えば、2−(4−モルホリニル)エトキシ、2−(4−モルホリニル)プロポキシ基等)、ヘテロ環(例えば、イミダゾリル、モルホリニル、ピペラジニル基等)、tert−ブトキシカルボキシピペラジン、カルボキシル基、C1−6アルキルカルボニルオキシ基(例えばアセトキシ、エチルカルボニルオキシ基等)、ハロゲン(例えば、フッ素、塩素、臭素およびヨウ素等)、シアノ、ニトロ、オキソ等が含まれる。これらの任意の置換基は置換可能な位置に1乃至5個置換していてもよく、置換基の数が2つ以上の場合、置換基は、それぞれ同じでも異なっていてもよい。
Cyc11で表わされる「5−6員の単環の不飽和炭素環」が含まれて、例えば、ベンゼン環等が含まれる。
基中、W1が、CHを表わすとき、CHの水素は、任意でR11に置換されていてもよい。
基中、W2が、CHを表わすとき、CHの水素は、任意でR11に置換されていてもよい。
基中、W3が、CHを表わすとき、CHの水素は、任意でR11に置換されていてもよい。
基中、W4が、CHを表わすとき、CHの水素は、任意でR11に置換されていてもよい。
基中、W5が、CHを表わすとき、CHの水素は、任意でR14、R15またはR16に置換されていてもよい。
より好ましくは、例えば、置換基を有していてもよいピペリジル、ピペラジニル等である。
(そして、式中、式(I−1−A−2)の化合物は、式(I−2)の化合物ではない。)
(そして、式中、式(I−1−A−2−1)の化合物は、式(I−2)の化合物ではない。)
(そして、式中、式(I−1−A−2−1−1)の化合物は、式(I−2)の化合物ではない。)
さらに、式(I−1)で表わされる化合物の好ましい化合物として、例えば、式(I−1−1)の化合物:
5−(3−ヒドロキシフェニル)−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−フラミド、
4−クロロ−3−メトキシ−N−({1−[(2−フェニル−1,3−チアゾール−5−イル)メチル]−4−ピペリジニル}メチル)ベンズアミド、
4−クロロ−N−[(1−{[3−(2−クロロフェニル)−5−イソオキサゾリル]メチル}−4−ピペリジニル)メチル]−3−メトキシベンズアミド、
4−クロロ−3−メトキシ−N−({1−[(5−フェニル−2−チエニル)メチル]−4−ピペリジニル}メチル)ベンズアミド、
4−クロロ−N−[(1−{[3−(4−フルオロフェニル)−5−イソオキサゾリル]メチル}−4−ピペリジニル)メチル]−3−メトキシベンズアミド、
4−クロロ−N−[(1−{[2−(2−クロロフェニル)−1,3−チアゾール−5−イル]メチル}−4−ピペリジニル)メチル]−3−メトキシベンズアミド、
4−クロロ−3−メトキシ−N−[(1−{[5−(2−ピリジニル)−2−チエニル]メチル}−4−ピペリジニル)メチル]ベンズアミド、
4−クロロ−3−メトキシ−N−({1−[(4−フェニル−2−フリル)メチル]−4−ピペリジニル}メチル)ベンズアミド、
4−クロロ−3−メトキシ−N−({1−[(3−フェニル−1,2,4−オキサジアゾール−5−イル)メチル]−4−ピペリジニル}メチル)ベンズアミド、
4−クロロ−3−メトキシ−N−[(1−{[5−(2−ピリジニル)−2−チエニル]スルホニル}−4−ピペリジニル)メチル]ベンズアミド、
5,6−ジクロロ−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1(2H)−イソキノリノン、
3−フェニル−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)イソオキサゾロ[4,5−d]ピリダジン−4−アミン、
N−[(1−{[3−(4−クロロフェニル)−5−イソオキサゾリル]メチル}−4−ピペリジニル)メチル]−3−フェニルイソオキサゾロ[4,5−d]ピリダジン−4−アミン、
N−[(1−{[3−(3−クロロフェニル)−5−イソオキサゾリル]メチル}−4−ピペリジニル)メチル]−3−フェニルイソオキサゾロ[4,5−d]ピリダジン−4−アミン、
N−[(1−{[3−(2−クロロフェニル)−5−イソオキサゾリル]メチル}−4−ピペリジニル)メチル]−3−フェニルイソオキサゾロ[4,5−d]ピリダジン−4−アミン、
3−フェニル−4−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メトキシ)イソオキサゾロ[4,5−d]ピリダジン、
4−アニリノ−2−[({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)アミノ]−5−ピリミジンカルボキサアミド、
メチル 6−ブロモ−1−オキソ−4−フェニル−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,2−ジヒドロ−3−イソキノリンカルボキシレート、
メチル 6−クロロ−1−オキソ−4−フェニル−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,2−ジヒドロ−3−イソキノリンカルボキシレート、
4−アミノ−5−シアノ−6−エトキシ−N−((1−((5−(ピリジン−2−イル)−1,3,4−チアジアゾール−2−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド、
(R)−4−アミノ−5−シアノ−6−(1−ヒドロキシプロパン−2−イルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド、
4−クロロ−3−メトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド、
4−アミノ−5−クロロ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル}−2−ピリジンカルボキサアミド、
4−アミノ−3,5−ジクロロ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド、
4−アミノ−5−シアノ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド、
3,4−ジクロロ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド、
4−クロロ−3−(2−ヒドロキシエトキシ)−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド、
N−(4−アミノ−5−シアノ−6−エトキシ−2−ピリジニル)−2−{1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}アセトアミド、
N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−5−(1H−1,2,4−トリアゾール−3−イル)−1H−インダゾール−3−アミン、
メチル 1−オキソ−4−フェニル−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,2−ジヒドロ−3−イソキノリンカルボキシレート、
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド、
4−アミノ−5−シアノ−N−((1−((4−((ジメチルアミノ)メチル)−2−フェニルチアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミド等である。
本発明において、式(I)で表わされる化合物は、塩を形成していてもよく、またN−オキシド体や四級アンモニウム塩であってもよい。さらにこれらの化合物は、溶媒和物であってもよい。式(I)で表わされる化合物の塩としては薬理学的に許容されるものすべてが含まれる。薬理学的に許容される塩は毒性のない、水溶性のものが好ましい。適当な塩として、例えば、アルカリ金属(例えば、カリウム、ナトリウム、リチウム等)の塩、アルカリ土類金属(例えば、カルシウム、マグネシウム等)の塩、アンモニウム塩(例えば、テトラメチルアンモニウム塩、テトラブチルアンモニウム塩等)、有機アミン(例えば、トリエチルアミン、メチルアミン、ジメチルアミン、シクロペンチルアミン、ベンジルアミン、フェネチルアミン、ピペリジン、モノエタノールアミン、ジエタノールアミン、トリス(ヒドロキシメチル)メチルアミン、リジン、アルギニン、N−メチル−D−グルカミン等)の塩、酸付加物塩[例えば、無機酸塩(例えば、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、リン酸塩、硝酸塩等)、有機酸塩(例えば、酢酸塩、トリフルオロ酢酸塩、乳酸塩、酒石酸塩、シュウ酸塩、フマル酸塩、マレイン酸塩、安息香酸塩、クエン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、イセチオン酸塩、グルクロン酸塩、グルコン酸塩等)等]等が含まれる。式(I)で表わされる化合物のN−オキシド体とは、式(I)で表わされる化合物の窒素原子が、酸化されたものを表わす。また、式(I)で表わされる化合物のN−オキシド体は、さらに上記の塩を形成していてもよい。式(I)で表わされる化合物の四級アンモニウム塩とは、式(I)で表わされる化合物の窒素原子が、R0基(R0基は、置換基を有していてもよいアルキル、アルケニル、アルキニル基(前記と同じ意味を表わす。)、置換基を有していてもよい環状基(前記と同じ意味を表わす。)を表わす。)によって四級化されたものを表わす。
式(I)で表わされる化合物の四級アンモニウム塩は、さらに上記の塩、上記のN−オキシド体を形成していてもよい。式(I)で表わされる化合物、その塩、そのN−オキシド体、その四級アンモニウム塩の適当な溶媒和物としては、例えば、水、アルコール系溶媒(エタノール等)等の溶媒和物等が挙げられる。溶媒和物は非毒性かつ水溶性であることが好ましい。式(I)で表わされる化合物は、公知の方法で上記の塩、上記のN−オキシド体、上記の四級アンモニウム塩、上記の溶媒和物に変換することができる。
式(I)で表わされる化合物は、例えば、以下に示す方法、これらに準ずる方法、実施例に示す方法、または公知の方法(例えば、Comprehensive Organic Transformations:A Guide to Functional Group Preparations,2nd Edition(Richard C. Larock, John Wiley&Sons Inc,1999)に記載された方法等)を適宜改良し、組み合わせて用いることによって製造することができる。なお、以下の各製造方法において、原料化合物は塩として用いてもよい。このような塩としては、前記した式(I)の塩として記載したものが用いられる。本発明の化合物は、例えば、以下の工程で製造することができる。
a) 式(I)の化合物のうち、Cyc3が、置換基を有していてもよい窒素含有ヘテロ環であり、Xが、メチレンであり、Zが、−N(R5)CO−である化合物、すなわち、式(I−A)の化合物:
Cyc12、Cyc22、Cyc32、R1−1、R2−1 およびR5−1中のカルボキシル、ヒドロキシ、アミノまたはチオールは、必要であれば、保護されていてもよい。)および式(I−C)で表わされる化合物:
(1)酸ハライドを用いる方法、
(2)混合酸無水物を用いる方法、
(3)縮合剤を用いる方法等が挙げられる。
(1)酸ハライドを用いる方法は、例えば、カルボン酸を有機溶媒(クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン等)中または無溶媒で、酸ハライド化剤(オキザリルクロライド、チオニルクロライド等)と−20℃〜還流温度で反応させ、得られた酸ハライドを塩基(ピリジン、トリエチルアミン、ジメチルアニリン、ジメチルアミノピリジン、ジイソプロピルエチルアミン等)の存在下、アミンと不活性有機溶媒(クロロホルム、ジクロロメタン、ジエチルエーテル、テトラヒドロフラン等)中、0〜40℃の温度で反応させることにより行なわれる。また、有機溶媒(ジオキサン、テトラヒドロフラン等)中、アルカリ水溶液(重曹水または水酸化ナトリウム溶液等)を用いて、酸ハライドと0〜40℃で反応させることにより行なうこともできる。
(1)アルカリ加水分解、
(2)酸性条件下における脱保護反応、
(3)加水素分解による脱保護反応、
(4)シリル基の脱保護反応、
(5)金属を用いた脱保護反応、
(6)金属錯体を用いた脱保護反応等が挙げられる。
(1)アルカリ加水分解による脱保護反応は、アルカリ金属の水酸化物(水酸化ナトリウム、水酸化カリウム、水酸化リチウム等)、アルカリ土類金属の水酸化物(水酸化バリウム、水酸化カルシウム等)または炭酸塩(炭酸ナトリウム、炭酸カリウム等)あるいはその水溶液もしくはこれらの混合物を用いて、約0〜40℃の温度で行なわれる。
b)式(I)の化合物において、式(I−G)の化合物:
ビス(ジメンジリデンアセトン)パラジウム、パラジウム黒、1,1’−ビス(ジフェニルホスフィノフェロセン)ジクロロパラジウム(PdCl2(dppf)2)、二塩化ジアリルパラジウム(PdCl2(allyl)2)、ヨウ化フェニルビス(トリフェニルホスフィン)パラジウム(PhPdI(PPh3)2)、トリス(ジベンジリデンアセトン)ジパラジウム(0)等)存在下、(S)−2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフチルまたは4,5−ビス(ジフェニルホスフィノ)−9,9−ジメチル−9H−キサンテンの存在下または非存在下、室温〜約120℃で反応させることにより行われる。
c) 式(I−J)の化合物:
d) 式(I)の化合物のうち、Cyc3は、置換基を有していてもよい窒素含有ヘテロ環であり、Xは、メチレンであり、R1およびR2はそれぞれ水素であり、Zは、−N(R5)CO−であり、R5およびCyc4の置換基が一緒になって、置換基を有していてもよいC1−4のアルキレンまたは置換基を有していてもよいC2−4のアルケニンである化合物、すなわち、式(I−O)の化合物:
パラ−トルエンスルホン酸を有機溶媒(例えば、トルエン、ジクロロメタン、ベンゼン、ジエチルエーテル、テトラヒドロフラン等)中、塩基(例えば、ピリジン、トリエチルアミン、ジメチルアニリン、ジメチルアミノピリジンまたはジイソプロピルエチルアミン等)存在下、0〜約40℃で反応させることにより行われる。
e) 式(I)の化合物のうち、Cyc3は、置換基を有していてもよい窒素含有ヘテロ環であり、Xは、メチレンであり、Zは、−N(R5)CO−であり、R5およびCyc4の置換基が一緒になって、メトキシカルボニルおよびフェニルを持つビニル基を形成している、すなわち、式(I−Y)の化合物:
f) 式(I)の化合物のうち、Cyc3は、置換基を有していてもよい窒素含有ヘテロ環であり、Xは、メチレンであり、Zは、結合手であり、R1およびR2は、それぞれ水素、Cyc4は、R13、フェニル、オキソを置換基として持つ1,4−ジヒドロキノリンである、すなわち、式(I−A−A)の化合物:
g) 式(I)の化合物のうち、Cyc3は、R10を持つピペリジン環であり、Xは、メチレンであり、R1およびR2は、それぞれ水素であり、Zは、−NHCO−であり、Cyc4は、R14、R15およびR16を持つベンゼンまたはピリジン環である、すなわち、式(I−1−5−A):
反応スキーム6において、式(I−F−1)で表わされる化合物から式(I−D−1)で表わされる化合物への反応は、還元的アミノ化反応である。
本発明化合物は、これらの反応により製造するか、またはその一部を改変して製造することができる。
後記に記載した生物学的実施例以外の薬理試験として、例えば、以下に示す方法がある。以下に示す方法によって、式(I)で表わされる化合物のin vivoでの効果を証明することができる。式(I)で表わされる化合物を動物へ投与するために用いる媒体は、化合物を、安全かつ投与可能な状態に懸濁または溶解できるものであればよく、例えば、当業者が化合物を動物に投与するために用いる媒体、例えば、メチルセルロース、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、プロピレングリコール、ポリエチレングリコール、糖、糖アルコール、食用油、蒸留水、生理食塩水およびこれらの混合物等を適宜選択して用いることができる。
(1)KKAyマウスを用いた糖尿病モデルにおけるインスリン抵抗性改善作用の検討
雄性KKAy/Ta Jclマウスを8週齢で入荷後、個別ケージにて約1週間の予備飼育を行う。予備飼育期間中および試験期間中は、固形飼料及び上水道水を給水瓶から自由摂取させる。実験開始当日(Day0)、体重を測定し、尾静脈からマイクロキャピラリーを用いて採血後、血糖値を測定する。血糖値を指標に層別無作為化法による群分けを行ない、1群あたり5匹を割り付けし、投薬を開始する。投薬は、例えば、被験薬を上記の媒体に懸濁または溶解後、ゾンデを用いて強制的に経口投与するか、またはシリンジを用いて皮下に非経口的に投与することで行うことができる。対照群には、媒体のみを投与することが好ましい。投与量および投与回数は、被験薬の効果によって適宜増減させることができるが、例えば、約0.1mg/kg体重乃至約100mg/kg体重を1日あたり1回乃至3回程度、連日投与することが好ましい。本モデルでの有効性の指標としては、体重、摂餌量、血糖値、血漿中トリグリセライド、インスリン値、肝臓重量等を用いることができ、これらの指標は投薬開始後、任意の日数が経過した後に測定することができる。例えば、投薬開始から2日後(Day2)乃至7日後(Day7)に、これらの指標を測定することで、本モデルでの有効性を確認することができる。本モデルにおいて一般的に対照薬として用いられるピオグリタゾン(Pioglitazone)は、例えば、50mg/kg体重を1日1回経口投与することで、体重の増加、血糖値の低下、インスリン値の低下等の有効性を示すことができる。
式(I)で表わされる化合物は、肝毒性等の望ましくない副作用を持たないため、化合物の毒性は十分に低いものである。従って、本発明の式(I)で表わされる化合物は、医薬品として使用するために十分安全であることが確認された。
式(I)で表わされる化合物、その塩、そのN−オキシド、その溶媒和物またはそのプロドラッグ(以下、本発明化合物とよぶことがある。)は、代謝性疾患(例えば、糖尿病(インスリン抵抗性糖尿病または非インスリン抵抗性糖尿病)、高脂血症、その他のインスリン抵抗性疾患等)、脳血管疾患(例えば、脳卒中、脳出血、くも膜下出血、ウィリス動脈輪閉塞症、慢性硬膜下血腫等)等の予防および/または治療剤として用いることができる。
もちろん前記したように、投与量は、種々の条件によって変動するので、前記投与量より少ない量で十分な場合もあるし、また範囲を越えて必要な場合もある。
5−(3−ヒドロキシフェニル)−2−フロイック アシッド
1H NMR (DMSO-d6): d 9.73 (s, 1H), 7.33-7.13 (m, 4H), 7.02 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 7.7 Hz, 1H);
Mass data (APCI, Neg.): m/z 203 (M - H)-.
実施例2:
メチル 4−アミノ−3,5−ジクロロ−6−エトキシ−2−ピリジンカルボキシレート
1H NMR (DMSO-d6): d 6.79 (s, 2H), 4.28 (q, J = 7.0 Hz, 2H), 3.86 (s, 3H), 1.29 (t, J = 7.0 Hz, 3H).
実施例3:
4−アミノ−3,5−ジクロロ−6−エトキシ−2−ピリジンカルボン酸
1H NMR (DMSO-d6): d 6.85 (s, 2H), 4.28 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.0 Hz, 3H);
Mass data (APCI, Neg.): m/z 249 (M - H)-.
実施例4:
2−クロロベンズアルデヒド オキシム
1H NMR (CDCl3): d 8.57 (s, 1H), 8.18-8.03 (bs, 1H), 7.83 (dd, J = 2.3, 7.8 Hz, 1H), 7.40 (dd, J = 1.6, 7.8 Hz, 1H), 7.35- 7.25 (m, 2H).
実施例5:
2−クロロ−N−ヒドロキシベンゼンカルボキシミドイル クロリド
1H NMR (CDCl3): d 9.02 (s, 1H), 7.49-7.43 (m, 2H), 7.41-7.36 (m, 1H), 7.34-7.29 (m, 1H).
実施例6:
[3−(2−クロロフェニル)−5−イソオキサゾリル]メタノール
1H NMR (CDCl3): d 7.74-7.69 (m, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.42-7.32 (s, 2H), 6.72 (s, 1H), 4.84 (s, 2H).
実施例7:
3−フェニル−5−イソオキサゾールカルバアルデヒド
1H NMR (DMSO-d6): d 9.97 (s, 1H), 8.06-7.91 (m, 3H), 7.64-7.47 (m, 3H).
実施例8:
tert−ブチル ({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)カルバメート
1H NMR (CDCl3): d 7.83-7.79 (m, 2H), 7.48-7.43 (m, 3H), 6.49 (s, 1H), 4.66-4.57 (m, 1H), 3.73 (s, 2H), 3.06-2.93 (m, 4H), 2.16-2.07 (m, 2H), 1.74-1.66 (m, 2H), 1.52-1.39 (m, 10H), 1.38-1.24 (m, 2H);
Mass data (ESI, Pos.): m/z 372 (M + H)+.
実施例9:
1−{1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メタンアミン
1H NMR (CDCl3): d 7.84-7.78 (m, 2H), 7.49-7.42 (m, 3H), 6.50 (s, 1H), 3.74 (s, 2H), 3.03-2.95 (m, 2H), 2.60-2.57 (m, 2H), 2.18-2.07 (m, 2H), 1.79-1.70 (m, 2H), 1.35-1.23 (m, 3H), 1.21-1.10 (m, 2H);
Mass data (ESI, Pos.): m/z 272 (M + H)+.
実施例10:
tert−ブチル 4−{[(4−クロロ−3−メトキシベンゾイル)アミノ]メチル}−1−ピペリジンカルボキシレート
1H NMR (DMSO-d6): d 8.60 (t, J = 5.7 Hz, 1H), 7.61-7.39 (m, 3H), 3.91 (m, 5H), 3.15 (t, J = 6.0 Hz, 2H), 2.81-2.62 (m, 2H), 1.72-1.51 (m, 3H), 1.39 (s, 9H), 1.12-0.92 (m, 2H);
Mass data (ESI, Pos.): m/z 283 (M -tert-butoxycarbonyl + H)+.
実施例11:
4−クロロ−3−メトキシ−N−(4−ピペリジニルメチル)ベンズアミド トリフルオロアセテート
1H NMR (DMSO-d6): d 8.68 (t, J = 5.8 Hz, 1H), 8.58-8.42 (m, 1H), 8.22-8.08 (m, 1H), 7.53-7.44 (m, 3H), 3.91 (s, 3H), 3.28-3.16 (m, 4H), 2.87-2.75 (m, 2H), 1.83-1.75 (m, 3H), 1.32 (d, J = 11.9 Hz, 2H);
Mass data (ESI, Pos.): m/z 283 (M + H)+.
実施例12:
2−(4−クロロフェニル)−1,3−チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.06 (s, 1H), 8.43 (s, 1H), 8.00-7.95 (m, 2H), 7.50-7.45 (m, 2H).
実施例13:
2−(2−クロロフェニル)−1,3−チアゾール−5−カルバアルデヒド
1H NMR (DMSO-d6): d 10.1 (s, 1H), 8.52 (s, 1H), 8.40-8.31 (m, 1H), 7.59-7.51 (m, 1H), 7.48-7.39 (m, 2H).
実施例14:
4−フェニル−2−フラルアルデヒド
1H NMR (DMSO-d6): d 9.66 (s, 1H), 8.64 (s, 1H), 8.05 (s, 1H), 7.72-7.61 (m, 2H), 7.40-7.28 (m, 3H).
実施例15:
5−(2−ピリジニル)−2−チオフェンカルバアルデヒド
1H NMR (DMSO-d6): d 9.94 (s, 1H), 8.62 (d, J = 4.0 Hz, 1H), 8.17-7.86 (m, 1H), 8.15-7.92 (m, 3H), 7.42 (dd, J =4.8, 7.5 Hz, 1H).
実施例16:
4−クロロ−3−メトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.87-7.74 (m, 2H), 7.53-7.33 (m, 5H), 7.18-7.11 (m, 1H), 6.49 (s, 1H), 6.23-6.13 (m, 1H), 3.96 (s, 3H), 3.74 (s, 2H), 3.41-3.32 (m, 2H), 3.03-2.94 (m, 2H), 2.20-2.09 (m, 2H), 1.82-1.72 (m, 2H), 1.69-1.61 (m, 1H), 1.47-1.32 (m, 2H);
Mass data (ESI, Pos.): m/z 440 (M+H)+.
実施例17:
2−アニリノ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,3−チアゾール−4−カルボキサアミド
1H NMR (CDCl3): d 7.87-7.75 (m, 2H), 7.48-7.42 (m, 4H), 7.41-7.31 (m, 4H), 7.29-7.20 (m, 1H), 7.15-7.08 (m, 2H), 6.49 (s, 1H), 3.73 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.99 (d, J = 11.2 Hz, 2H), 2.14 (t, J = 11.4 Hz, 2H), 1.82-1.73 (m, 2H), 1.69-1.58 (m, 1H), 1.48-1.35 (m, 2H);
Mass data (ESI, Pos.): m/z 474 (M + H)+.
実施例18:
4−クロロ−2−メトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 8.14 (d, J = 8.4 Hz, 1H), 7.87-7.71 (m, 3H), 7.53-7.39 (m, 3H), 7.09-7.04 (m, 1H), 6.97 (s, 1H), 6.49 (s, 1H), 3.97 (s, 3H), 3.74 (s, 2H), 3.37 (t, J = 6.3 Hz, 2H), 2.99 (d, J = 11.3 Hz, 2H), 2.15 (t, J = 11.5 Hz, 2H), 1.77 (d, J = 12.7 Hz, 2H), 1.69-1.55 (m, 1H), 1.47-1.33 (m, 2H);
Mass data (ESI, Pos.): m/z 440 (M + H)+.
実施例19:
5−(4−クロロフェニル)−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−フルアミド
1H NMR (DMSO-d6): d 7.94-7.83 (m, 2H), 7.63 (d, J = 8.6 Hz, 2H) 7.42-7.12 (m, 6H), 6.73 (d, J = 3.6 Hz, 1H), 6.28 (m, 2H), 3.74 (s, 2H), 3.38 (t, J = 6.4 Hz, 2H), 3.00 (d, J = 11.4 Hz, 2H), 2.21-2.08 (m, 2H), 1.80 (d, J = 12.7 Hz, 2H), 1.71-1.61 (m, 1H), 1.43 (dd, J = 12.02, 3.04 Hz, 2H);
Mass data (ESI, Pos.): m/z 476 (M + H)+.
実施例20:
N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1H−インドール−6−カルボキサアミド
1H NMR (CDCl3): d 8.49-8.37 (m, 1H), 7.99 (s, 1H), 7.87-7.74 (m, 2H), 7.68-7.62 (m, 1H), 7.49-7.38 (m, 4H), 7.36-7.30 (s, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 6.32-6.19 (m, 1H), 3.74 (s, 2H), 3.46-3.36 (m, 2H), 3.03-2.94 (m, 2H), 2.23-2.09 (m, 2H), 1.85-1.76 (m, 2H), 1.74-1.61 (m, 1H), 1.50-1.35 (m, 2H);
Mass data (ESI, Pos.): m/z 415 (M + H)+.
実施例21:
5−(3−ヒドロキシフェニル)−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−フルアミド
1H NMR (CD3OD): d 7.83 (dd, J = 2.5, 6.2 Hz, 2H), 7.53-7.41 (m, 3H), 7.34-7.16 (m, 4H), 6.89-6.72 (m, 3H), 3.78 (s, 2H), 3.40-3.31 (m, 2H), 3.01 (d, J = 11.5 Hz, 2H), 2.20 (t, J = 10.1 Hz, 2H), 1.87-1.62 (m, 3H), 1.49-1.33 (m, 2H);
Mass data (APCI, Pos.): m/z 458 (M + H)+.
実施例22:
5−フェニル−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−フルアミド
1H NMR (CDCl3): d 7.84-7.76 (m, 2H), 7.74-7.67 (m, 2H), 7.47-7.38 (m, 5H), 7.36-7.31 (m, 1H), 7.20-7.15 (m, 1H), 6.76-6.71 (m, 1H), 6.52-6.42 (m, 2H), 3.76-3.71 (m, 2H), 3.42-3.34 (m, 2H), 3.04-2.95 (m, 2H), 2.21-2.10 (m, 2H), 1.85-1.76 (m, 2H), 1.72-1.61 (m, 1H), 1.49-1.37 (m, 2H);
Mass data (ESI, Pos.): m/z 442 (M + H)+.
実施例23:
N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル]−3−(3−ピリジニル)ベンズアミド
1H NMR (DMSO-d6): d 8.87 (s, 1H), 8.60-8.52 (m, 1H), 8.18-8.01 (m, 2H), 7.91-7.79 (m, 4H), 7.64-7.43 (m, 5H), 6.50 (s, 1H), 6.79 (s, 1H), 3.78 (s, 2H), 3.37-3.31 (m, 2H), 3.07-2.97 (m, 2H), 2.25-2.13 (m, 2H), 1.86-1.63 (m, 3H), 1.48-1.34 (m, 2H);
Mass data (ESI, Pos.): m/z 453 (M + H)+.
実施例24:
4−アミノ−5−クロロ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド
1H NMR (DMSO-d6): d 8.34 (t, J = 6.2 Hz, 1H), 7.87 (dd, J = 2.9, 6.4 Hz, 2H), 7.52-7.47 (m, 3H), 7.09 (s, 1H), 6.94 (s, 1H), 6.68-6.59 (br s, 2H), 4.42 (q, J = 7.0 Hz, 2H), 3.70 (s, 2H), 3.28-3.09 (m, 2H), 2.87 (d, J = 11.1 Hz, 1H), 2.03 (t, J = 10.7 Hz, 2H), 1.62 (d, J = 11.7 Hz, 2H), 1.57-1.48 (m, 1H), 1.34-1.17 (m, 5H);
Mass data (APCI, Pos.): m/z 470 (M + H)+.
実施例25:
4−アミノ−3,5−ジクロロ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド
1H NMR (DMSO-d6): d 8.36 (t, J = 6.2 Hz, 1H), 7.87 (dd, J = 2.9, 6.5 Hz, 2H), 7.61-7.44 (m, 3H), 6.94 (s, 1H), 6.64-6.58 (br s, 2H), 4.31 (q, J = 7.0 Hz, 2H), 3.71 (s, 2H), 3.10 (t, J = 6.3 Hz, 2H), 2.88 (d, J = 11.5 Hz, 2H), 2.04 (t, J = 10.6 Hz, 2H), 1.69 (d, J = 10.9 Hz, 2H), 1.55-1.45 (m, 1H), 1.31-1.21 (m, 5H);
Mass data (APCI, Pos.): m/z 504 (M + H)+.
実施例26:
4−アミノ−5−シアノ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド
1H NMR (CDCl3): d 7.84-7.76 (m, 3H), 7.50-7.41 (m, 3H), 7.19 (s, 1H), 6.48 (s, 1H), 5.11 (s, 2H), 4.43 (q, J= 7.1 Hz, 2H), 3.74 (s, 2H), 3.38-3.31 (m, 2H), 3.02-2.95 (m, 2H), 2.19-2.09 (m, 2H), 1.80-1.70 (m, 2H), 1.66-1.54 (m, 1H), 1.47-1.34 (m, 5H);
Mass data (ESI, Pos.): m/z 461 (M + H)+.
実施例27:
5−クロロ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド
1H NMR (CDCl3): d 8.50-8.47 (m, 1H), 8.15 (d, J = 8.6 Hz, 1H), 8.03-7.97 (m, 1H), 7.84-7.77 (m, 3H), 7.49-7.42 (m, 3H), 6.49 (s, 1H), 3.73 (s, 2H), 3.38 (t, J = 6.3 Hz, 2H), 3.04-2.95 (m, 2H), 2.20-2.10 (m, 2H), 1.83-1.74 (m, 2H), 1.71-1.62 (m, 1H), 1.50-1.36 (m, 2H);
Mass data (ESI, Pos.): m/z 411 (M + H)+.
実施例28:
3,4−ジクロロ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.87 (m, 1H), 7.84-7.76 (m, 2H), 7.62-7.55 (m, 1H), 7.52-7.41 (m, 4H), 6.49 (s, 1H), 6.33-6.26 (m, 1H), 3.73 (s, 2H), 3.38-3.31 (m, 2H), 3.03-2.93 (m, 2H), 2.20-2.07 (m, 2H), 1.82-1.70 (m, 2H), 1.69-1.57 (m, 1H), 1.46-1.31 (m, 2H);
Mass data (ESI, Pos.): m/z 444 (M+H)+.
実施例29:
3,5−ジクロロ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.83-7.78 (m, 2H), 7.62-7.61 (m, 2H), 7.49-7.43 (m, 4H), 6.49 (s, 1H), 6.16-6.10 (m, 1H), 3.74 (s, 2H), 3.36 (t, J = 6.4 Hz, 2H), 3.02-2.97 (m, 2H), 2.18-2.11 (m, 2H), 1.80-1.73 (m, 2H), 1.68-1.60 (m, 1H), 1.46-1.35 (m, 2H);
Mass data (APCI, Pos.): m/z 444 (M + H)+.
実施例30:
5−クロロ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−チオフェンカルボキサアミド
1H NMR (CDCl3): d 7.83-7.78 (m, 2H), 7.48-7.43 (m, 3H), 7.24 (d, J= 3.9 Hz, 1H), 6.88 (d, J = 3.9 Hz, 1H), 6.49 (s, 1H), 6.05-5.98 (m, 1H), 3.73 (s, 2H), 3.31 (t, J = 6.2 Hz, 2H), 3.01-2.94 (m, 2H), 2.17-2.09 (m, 2H), 1.78-1.71 (m, 2H), 1.67-1.55 (m, 1H), 1.44-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 416 (M + H)+.
実施例31:
2−メチル−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,3−ベンゾチアゾール−6−カルボキサアミド
1H NMR (CDCl3): d 8.27 (s, 1H), 7.91-7.85 (m, 1H), 7.84-7.77 (m, 3H), 7.48-7.41 (m, 3H), 6.50 (s, 1H), 6.30-6.22 (m, 1H), 3.74 (s, 2H), 3.45-3.37 (m, 2H), 3.04-2.95 (m, 2H), 2.86 (s, 3H), 2.21-2.10 (m, 2H), 1.84-1.75 (m, 2H), 1.72-1.62 (m, 1H), 1.49-1.37 (m, 2H);
Mass data (ESI, Pos.): m/z 447 (M + H)+.
実施例32:
4−フルオロ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.83-7.73 (m, 4H), 7.48-7.42 (m, 3H), 7.10 (t, J= 8.6 Hz, 2H), 6.49 (s, 1H), 6.20-6.10 (m, 1H), 3.74 (s, 2H), 3.36 (t, J = 6.3 Hz, 2H), 3.03-2.94 (m, 2H), 2.20-2.08 (m, 2H), 1.82-1.73 (m, 2H), 1.71-1.58 (m, 1H), 1.47-1.35 (m, 2H);
Mass data (ESI, Pos.): m/z 394 (M + H)+.
実施例33:
N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−(3−ピリジニル)−1,3−チアゾール−4−カルボキサアミド
1H NMR (CDCl3): d 9.21-9.17 (m, 1H), 8.73-8.68 (m, 1H), 8.26-8.19 (m, 1H), 8.18-8.16 (m, 1H), 7.83-7.77 (m, 2H), 7.55-7.38 (m, 5H), 6.49 (s, 1H), 3.74 (s, 2H), 3.45-3.48 (m, 2H), 3.04-2.94 (m, 2H), 2.22-2.11 (m, 2H), 1.86-1.77 (m, 2H), 1.74-1.62 (m, 1H), 1.52-1.38 (m, 2H);
Mass data (ESI, Pos.): m/z 460 (M + H)+.
実施例34:
4−シアノ−3−メトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.84-7.77 (m, 2H), 7.63-7.58 (m, 1H), 7.51-7.41 (m, 4H), 7.24-7.20 (m, 1H), 6.48 (s, 1H), 6.26-6.13 (m, 1H), 3.99 (s, 3H), 3.74 (s, 2H), 3.42-3.34 (m, 2H), 3.04-2.92 (m, 2H), 2.20-2.10 (m, 2H), 1.81-1.72 (m, 2H), 1.71-1.60 (m, 1H), 1.49-1.35 (m, 2H);
Mass data (ESI, Pos.): m/z 431 (M + H)+.
実施例35:
4−クロロ−3−メトキシ−N−({1−[(4−フェニル−2−チエニル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.63-7.08 (m, 10H), 6.15 (s, 1H), 3.96 (s, 3H), 3.74 (s, 2H), 3.37 (t, J = 6.3 Hz, 2H), 3.00 (d, J = 11.5 Hz, 2H), 2.05 (t, J = 11.6 Hz, 2H), 1.76-1.25 (m, 5H);
Mass data (ESI, Pos.): m/z 455 (M + H)+.
実施例36:
4−クロロ−3−メトキシ−N−({1−[(2−フェニル−1,3−チアゾール−5−イル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CD3OD): d 7.96-7.85 (m, 2H), 7.68 (s, 1H), 7.55-7.31 (m, 6H), 3.94 (s, 3H), 3.82 (s, 2H), 3.40-3.22 (m, 2H), 3.00 (d, J = 11.4 Hz, 2H), 2.11 (t, J = 10.9 Hz, 2H), 1.78 (d, J = 13.5 Hz, 2H), 1.74-1.62 (m, 1H), 1.45-1.29 (m, 2H);
Mass data (APCI, Pos.): m/z 456 (M + H)+.
実施例37:
4−クロロ−3−メトキシ−N−({1−[(1−フェニル−1H−ピラゾール−4−イル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CD3OD): d 8.18 (s, 1H), 7.74-7.69 (m, 3H), 7.52-7.31 (m, 6H), 3.94 (s, 3H), 3.59 (s, 2H), 3.34-3.27 (m, 2H), 3.04 (d, J = 11.5 Hz, 2H), 2.13 (t, J = 11.2 Hz, 2H), 1.78 (d, J = 11.2 Hz, 2H), 1.74-1.64 (m, 1H), 1.46-1.24 (m, 2H);
Mass data (APCI, Pos.): m/z 439 (M + H)+.
実施例38:
4−クロロ−N−[(1−{[3−(4−クロロフェニル)−5−イソオキサゾリル]メチル]−4−ピペリジニル)メチル]−3−メトキシベンズアミド
1H NMR (CD3OD): d 7.83 (d, J = 8.6 Hz, 2H), 7.55-7.30 (m, 5H), 6.79 (s, 1H), 3.94 (s, 3H), 3.78 (s, 2H), 3.38-3.20 (m, 2H), 3.00 (d, J = 11.6 Hz, 2H), 2.18 (t, J = 11.5 Hz, 2H), 1.78 (d, J = 11.9 Hz, 2H), 1.69-1.62 (m, 1H), 1.38 (dd, J= 12.3, 3.4 Hz, 2H);
Mass data (APCI, Pos.): m/z 474 (M + H)+.
実施例39:
4−クロロ−N−[(1−{[3−(3−クロロフェニル)−5−イソオキサゾリル]メチル]−4−ピペリジニル)メチル]−3−メトキシベンズアミド
1H NMR (CD3OD): d 7.87 (s, 1H), 7.78-7.76 (m, 1H), 7.54-7.31 (m, 5H), 6.82 (s, 1H), 3.94 (s, 3H), 3.78 (s, 2H), 3.38-3.20 (m, 2H), 3.00 (d, J = 11.6 Hz, 2H), 2.18 (t, J = 2.1 Hz, 2H), 1.77 (d, J = 11.3 Hz, 2H), 1.69-1.62 (m, 1H), 1.44-1.24 (m, 2H);
Mass data (APCI, Pos.): m/z 474 (M + H)+.
実施例40:
4−クロロ−N−[(1−{[3−(2−クロロフェニル)−5−イソオキサゾリル]メチル]−4−ピペリジニル)メチル]−3−メトキシベンズアミド
1H NMR (CD3OD): d 7.67 (dd, J = 1.8, 7.5 Hz, 1H), 7.74-7.31 (m, 6H), 6.78 (s, 1H), 3.94 (s, 3H), 3.78 (s, 2H), 3.38-3.20 (m, 2H), 3.01 (d, J = 11.6 Hz, 2H), 2.19 (t, J = 2.1 Hz, 2H), 1.77 (d, J = 11.3 Hz, 2H), 1.69-1.62 (m, 1H), 1.48-1.24 (m, 2H);
Mass data (APCI, Pos.): m/z 474 (M + H)+.
実施例41:
4−クロロ−3−メトキシ−N−({1−[(5−フェニル−2−チエニル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.61-7.54 (m, 2H), 7.49-7.45 (m, 1H), 7.42-7.32 (m, 3H), 7.18-7.11 (m, 2H), 6.88-6.84 (m, 1H), 6.19-6.11 (m, 1H), 3.96 (s, 3H), 3.71 (s, 2H), 3.40-3.33 (m, 2H), 3.05-2.96 (m, 2H), 2.09-1.99 (m, 2H), 1.80-1.71 (m, 2H), 1.69-1.59 (m, 1H), 1.47-1.32 (m, 2H);
Mass data (ESI, Pos.): m/z 455 (M + H)+.
実施例42:
4−クロロ−3−メトキシ−N−({1−[(5−メチル−4−フェニル−2−チエニル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CD3OD): d 7.55-7.48 (m, 1H), 7.44-7.21 (m, 7H), 6.90 (s, 1H), 3.94 (s, 3H), 3.78 (s, 2H), 3.38-3.20 (m, 2H), 3.01 (d, J = 11.5 Hz, 2H), 2.44 (s, 3H), 2.09 (t, J = 11.1 Hz, 2H), 1.77 (d, J = 12.3 Hz, 2H), 1.69-1.62 (m, 1H), 1.48-1.24 (m, 2H);
Mass data (APCI, Pos.): m/z 469 (M + H)+.
実施例43:
4−クロロ−N−[(1−{[2−(4−クロロフェニル)−1,3−チアゾール−5−イル]メチル]−4−ピペリジニル)メチル]−3−メトキシベンズアミド
1H NMR (CDCl3): d 7.88-7.82 (m, 2H), 7.61 (s, 1H), 7.47 (s, 1H), 7.43-7.36 (m, 3H), 7.17-7.11 (m, 1H), 6.18-6.12 (m, 1H), 3.96 (s, 3H), 3.74 (s, 2H), 3.40-3.33 (m, 2H), 3.00-2.93 (m, 2H), 2.11-2.00 (m, 2H), 1.80-1.71 (m, 2H), 1.70-1.60 (m, 1H), 1.43-1.31 (m, 2H);
Mass data (ESI, Pos.): m/z 490 (M+H)+.
実施例44:
4−クロロ−N−[(1−{[3−(4−フルオロフェニル)−5−イソオキサゾリル]メチル]−4−ピペリジニル)メチル]−3−メトキシベンズアミド
1H NMR (CD3OD): d 7.56 (dd, J = 5.4, 8.2 Hz, 2H), 7.54-7.29 (m, 3H), 7.21 (t, J = 8.6 Hz, 2H), 6.79 (s, 1H), 3.94 (s, 3H), 3.78 (s, 2H), 3.38-3.20 (m, 2H), 3.07 (d, J = 11.3 Hz, 2H), 2.09 (t, J 11.1 Hz, 2H), 1.77 (d, J = 12.3 Hz, 2H), 1.69-1.62 (m, 1H), 1.48-1.24 (m, 2H);
Mass data (APCI, Pos.): m/z 458 (M + H)+.
実施例45:
4−クロロ−N−[(1−{[2−(2−クロロフェニル)−1,3−チアゾール−5−イル]メチル]−4−ピペリジニル)メチル]−3−メトキシベンズアミド
1H NMR (CDCl3): d 8.21-8.16 (m, 1H), 7.71 (s, 1H), 7.52-7.45 (m, 2H), 7.43-7.30 (m, 3H), 7.17-7.11 (m, 1H), 6.19-6.12 (m, 1H), 3.96 (s, 3H), 3.80 (s, 2H), 3.40-3.33 (m, 2H), 3.03-2.94 (m, 2H), 2.12-2.02 (m, 2H), 1.80-1.71 (m, 2H), 1.70-1.58 (m, 1H), 1.46-1.32 (m, 2H);
Mass data (ESI, Pos.): m/z 490 (M + H)+.
実施例46:
4−クロロ−3−メトキシ−N−[(1−{[5−(2−ピリジニル)−2−チエニル]メチル]−4−ピペリジニル)メチル]ベンズアミド
1H NMR (CD3OD): d 8.45 (d, J = 4.9 Hz, 1H), 7.85-7.67 (m, 2H), 7.60-7.29 (m, 4H), 7.22 (t, J = 5.8 Hz, 2H), 6.98 (d, J = 3.6 Hz, 1H), 3.93 (s, 3H), 3.74 (s, 2H), 3.27 (d, J = 6.7 Hz, 2H), 3.00 (d, J = 11.5 Hz, 2H), 2.09 (t, J = 10.9 Hz, 2H), 1.76 (d, J = 6.7 Hz, 2H), 1.69-1.62 (m, 1H), 1.36 (m, 2H);
Mass data (APCI, Pos.): m/z 456 (M + H)+.
実施例47:
N−{[1−(4−ビフェニリルメチル)−4−ピペリジニル]メチル]−4−クロロ−3−メトキシベンズアミド
1H NMR (CDCl3): d 7.62-7.51 (m, 4H), 7.49-7.30 (m, 7H), 7.17-7.10 (m, 1H), 6.19-6.10 (m, 1H), 3.96 (s, 3H), 3.54 (s, 2H), 3.40-3.33 (m, 2H), 3.00-2.90 (m, 2H), 2.05-1.95 (m, 2H), 1.78-1.70 (m, 2H), 1.69-1.60 (m, 1H), 1.44-1.32 (m, 2H);
Mass data (ESI, Pos.): m/z 449 (M + H)+.
実施例48:
4−クロロ−3−メトキシ−N−({1−[4−(1−ピロリジニル)ベンジル
]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.48-7.44 (m, 1H), 7.41-7.36 (m, 1H), 7.17-7.10 (m, 3H), 6.55-6.48 (m, 2H), 6.16-6.09 (m, 1H), 3.96 (s, 3H), 3.41 (s, 2H), 3.38-3.31 (m, 2H), 3.29-3.23 (m, 4H), 2.96-2.87 (m, 2H), 2.02-1.87 (m, 6H), 1.75-1.66 (m, 2H), 1.65-1.51 (m, 1H), 1.42-1.29 (m, 2H);
Mass data (ESI, Pos.): m/z 442 (M + H)+.
実施例49:
4−クロロ−3−メトキシ−N−({1−[(4−フェニル−2−フリル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (DMSO-d6): d 8.56 (t, J = 9.0 Hz, 1H), 8.09 (s, 1H), 7.60-7.54 (m, 3H), 7.51 (d, J = 8.6 Hz, 1H), 7.46-7.42 (m, 1H), 7.39-7.34 (m, 2H), 7.27-7.21 (m, 1H), 6.74 (s, 1H), 3.91 (s, 3H), 3.48 (s, 2H), 3.17-3.11 (m, 2H), 2.88-2.80 (m, 2H), 1.99-1.90 (m, 2H), 1.69-1.61 (m, 2H), 1.58-1.47 (m, 1H), 1.24-1.12 (m, 2H);
Mass data (APCI, Pos.): m/z 439 (M + H)+.
実施例50:
4−クロロ−3−メトキシ−N−({1−[(5−フェニル−1,3,4−オキサジアゾール−2−イル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 8.10-8.04 (m, 2H), 7.57-7.44 (m, 4H), 7.41-7.36 (m, 1H), 7.18-7.11 (m, 1H), 6.20-6.11 (m, 1H), 3.96 (s, 3H), 3.74 (s, 2H), 3.41-3.34 (m, 2H), 3.08-2.99 (m, 2H), 2.30-2.19 (m, 2H), 1.83-1.73 (m, 2H), 1.69-1.60 (m, 1H), 1.49-1.35 (m, 2H);
Mass data (ESI, Pos.): m/z 441 (M + H)+.
実施例51:
4−クロロ−3−メトキシ−N−({1−[(3−フェニル−1,2,4−オキサジアゾール−5−イル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CD3OD): d 8.18-8.12 (m, 2H), 7.70-7.63 (m, 1H), 7.62-7.55 (m, 2H), 7.52-7.47 (m, 1H), 7.46-7.40 (m, 1H), 7.39-7.34 (m, 1H), 3.94 (s, 3H), 3.77 (s, 2H), 3.34-3.24 (m, 2H), 3.11-3.02 (m, 2H), 2.30-2.19 (m, 2H), 1.83-1.74 (m, 2H), 1.73-1.63 (m, 1H), 1.46-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 441 (M + H)+.
実施例52:
4−クロロ−3−メトキシ−N−({1−[(2−フェニル−1,3−チアゾール−4−イル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.97-7.92 (m, 2H), 7.49-7.36 (m, 5H), 7.18-7.11 (m, 2H), 6.19-6.12 (m, 1H), 3.96 (s, 3H), 3.75 (s, 2H), 3.40-3.33 (m, 2H), 3.10-3.02 (m, 2H), 2.18-2.07 (m, 2H), 1.80-1.72 (m, 2H), 1.70-1.55 (m, 1H), 1.50-1.36 (m, 2H);
Mass data (ESI, Pos.): m/z 456 (M + H)+.
実施例53:
4−クロロ−N−[(1−{[3−(2,6−ジクロロフェニル)−5−イソオキサゾリル]メチル]−4−ピペリジニル)メチル]−3−メトキシベンズアミド
1H NMR (DMSO-d6): d 8.57-8.50 (m, 1H), 7.68-7.62 (m, 2H), 7.60-7.40 (m, 4H), 6.61 (s, 1H), 3.91 (s, 3H), 3.77 (s, 2H), 3.19-3.13 (m, 2H), 2.91-2.83 (m, 2H), 2.09-2.00 (m, 2H), 1.71-1.64 (m, 2H), 1.59-1.47 (m, 1H), 1.29-1.16 (m, 2H);
Mass data (APCI, Pos.): m/z 508 (M + H)+.
実施例54:
2−クロロ−5−{[({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)アミノ]カルボニル}フェニル エチルカルボネート
1H NMR (CDCl3): d 7.84-7.77 (m, 2H), 7.66-7.57 (m, 2H), 7.55-7.41 (m, 4H), 6.49 (s, 1H), 6.21-6.11 (m, 1H), 4.40-4.32 (m, 2H), 3.74 (s, 2H), 3.39-3.20 (m, 2H), 3.03-2.94 (m, 2H), 2.18-2.09 (m, 2H), 1.81-1.71 (m, 2H), 1.68-1.55 (m, 1H), 1.44-1.36 (m, 5H);
Mass data (APCI, Pos.): m/z 498 (M + H)+.
実施例55:
4−クロロ−3−ヒドロキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.84-7.78 (m, 2H), 7.48-7.36 (m, 7H), 6.50 (s, 1H), 6.18-6.09 (m, 1H), 3.75 (s, 2H), 3.39-3.33 (m, 2H), 3.05-2.95 (m, 2H), 2.21-2.07 (m, 2H), 1.81-1.71 (m, 2H), 1.69-1.58 (m, 1H), 1.48-1.35 (m, 2H);
Mass data (APCI, Pos.): m/z 426 (M + H)+.
実施例56:
4−クロロ−3−(2−ヒドロキシエトキシ)−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (CDCl3): d 7.85-7.77 (m, 2H), 7.51-7.38 (m, 5H), 7.22-7.15 (m, 1H), 6.50 (s, 1H), 6.24-6.17 (m, 1H), 4.26-4.18 (m, 2H), 4.06-3.98 (m, 2H), 3.75 (s, 2H), 3.41-3.31 (m, 2H), 3.05-2.94 (m, 2H), 2.19-2.09 (m, 2H), 1.81-1.71 (m, 2H), 1.68-1.55 (m, 2H), 1.47-1.34 (m, 2H);
Mass data (APCI, Pos.): m/z 470 (M + H)+.
実施例57:
エチル {1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}アセテート
1H NMR (CDCl3): d 7.86-7.76 (m, 2H), 7.50-7.40 (m, 3H), 6.49 (s, 1H), 4.12 (q, J = 7.1 Hz, 1H), 3.73 (s, 2H), 3.00-2.90 (m, 2H), 2.27-2.11 (m, 4H), 2.09-2.01 (m, 1H), 1.86-1.67 (m, 3H), 1.44-1.30 (m, 2H), 1.29-1.20 (m, 3H);
Mass data (APCI, Pos.): m/z 329 (M + H)+.
実施例58:
{1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}アセチックアシッド 塩酸塩
1H NMR (DMSO-d6): d 11.26-11.11 (m, 1H), 7.94-7.85 (m, 2H), 7.61-7.50 (m, 3H), 7.37 (s, 1H), 4.56 (s, 2H), 3.51-3.39 (m, 2H), 3.12-2.97 (m, 2H), 2.23-2.15 (m, 2H), 1.99-1.82 (m, 3H), 1.65-1.49 (m, 2H).
実施例59:
{1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}アセチルクロライド 塩酸塩
1H NMR (DMSO-d6): d 7.92-7.81 (m, 2H), 7.62-7.48 (m, 3H), 7.38 (s, 1H), 4.59 (s, 2H), 3.50-3.36 (m, 2H), 3.12-2.97 (m, 2H), 2.22-2.09 (m, 2H), 1.99-1.79 (m, 3H), 1.67-1.50 (m, 2H).
実施例60:
N−(4−アミノ−5−シアノ−6−エトキシ−2−ピリジニル)−2−{1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}アセトアミド
1H NMR (CDCl3): d 7.85-7.76 (m, 2H), 7.50-7.41 (m, 4H), 7.24 (s, 1H), 6.48 (s, 1H), 4.91-4.84 (m, 2H), 4.32 (q, J = 6.7 Hz, 2H), 3.77-3.71 (m, 2H), 3.00-2.92 (m, 2H), 2.30-2.27 (m, 2H), 2.23-2.12 (m, 2H), 1.96-1.84 (m, 1H), 1.84-1.74 (m, 2H), 1.42-1.33 (m, 5H).
Mass data (APCI, Pos.): m/z 461 (M + H)+.
実施例61:
tert−ブチル 4−[(6−クロロ−1−オキソ−3,4−ジヒドロ−2(1H)−イソキノリニル)メチル]−1−ピペリジンカルボキシレート
1H NMR (CDCl3): d 8.00 (d, J = 8.3 Hz, 1H), 7.31 (dd, J = 8.3, 1.9 Hz, 1H), 7.18 (s, 1H), 3.57 (t, J = 6.5 Hz, 1H), 3.44 (t, J = 6.1 Hz, 2H), 3.30 (d, J = 6.1 Hz, 2H), 2.98 (t, J = 6.5 Hz, 1H), 2.72-2.62 (m, 2H), 2.28-2.18 (m, 2H), 1.83-1.73 (m, 2H), 1.68 (d, J = 12.3 Hz, 1H), 1.46 (s, 9H), 1.22 (m, 2H);
Mass data (APCI, Pos.): m/z 379 (M + H)+.
実施例62:
6−クロロ−2−(4−ピペリジニルメチル)−3,4−ジヒドロ−1(2H)−イソキノリノン トリフルオロアセテート
1H NMR (DMSO-d6): d 8.44-8.21 (m, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.49-7.35 (m, 2H), 3.52 (d, J = 5.8 Hz, 2H), 3.45 (d, J = 6.4 Hz, 2H), 3.16-3.12 (m, 2H), 2.87-2.81 (m, 2H), 2.36 (t, J = 6.0 Hz, 2H), 2.06-1.81 (m, 3H), 1.50-1.19 (m, 2H);
Mass data (ESI, Pos.): m/z 279 (M + H)+.
実施例63:
6−クロロ−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−3,4−ジヒドロ−1(2H)−イソキノリノン
1H NMR (CD3OD): d 7.86-7.79 (m, 3H), 7.36-7.25 (m, 5H), 6.78 (s, 1H), 3.78-3.72 (m, 2H), 3.61 (t, J = 6.6 Hz, 2H), 3.46 (d, J = 7.3 Hz, 2H), 3.31-3.25 (m, 2H), 3.01 (t, J = 6.2 Hz, 2H), 2.19 (t, J = 10.8 Hz, 2H), 1.78-1.81 (m, 3H), 1.42-1.28 (m, 2H);
Mass data (APCI, Pos.): m/z 436 (M + H)+.
実施例64:
{1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メタノール
Mass data (ESI, Pos.): m/z 273 (M + H)+.
実施例65:
{1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル 4−メチルベンゼンスルホネート
1H NMR (CDCl3): d 7.82-7.75 (m, 4H), 7.48-7.42 (m, 3H), 7.37-7.31 (m, 2H), 6.47 (s, 1H), 3.86 (d, J = 6.2 Hz, 2H), 3.70 (s, 2H), 2.98-2.89 (m, 2H), 2.45 (s, 3H), 2.14-2.15 (m, 2H), 1.73-1.64 (m, 3H), 1.35-1.22 (m, 2H);
Mass data (APCI, Pos.): m/z 427 (M + H)+.
実施例66:
4−フェニル−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−3,4−ジヒドロ−1(2H)−イソキノリノン
1H NMR (CD3OD): d 8.04 (d, J = 6.7 Hz, 1H), 7.82-7.76 (m, 2H), 7.45-7.04 (m, 11H), 6.75 (d, J = 7.1 Hz, 1H), 4.35 (d, J = 4.3 Hz, 2H), 3.95 (t, J = 11.5 Hz, 1H), 3.73-3.62 (m, 2H), 3.12-3.06 (m, 2H), 2.81-2.67 (m, 2H), 2.18-1.84 (m, 3H), 1.43-1.22 (m, 4H);
Mass data (APCI, Pos.): m/z 478 (M + H)+.
実施例67:
4−クロロ−3−メトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)カルボニル]−4−ピペリジニル}メチル)ベンズアミド
1H NMR (DMSO-d6): d 8.63 (t, J = 5.6 Hz, 1H), 7.92 (dd, J = 1.9, 7.6 Hz, 2H), 7.63-7.42 (m, 5H), 7.27 (s, 1H), 4.49 (d, J = 12.8 Hz, 1H), 3.97 (d, J = 13.3 Hz, 1H), 3.91 (s, 3H), 3.20 (d, J = 6.3 Hz, 2H), 3.13 (t, J = 12.2 Hz, 1H), 2.85 (t, J = 11.3 Hz, 1H), 1.99-1.72 (m, 3H), 1.24-1.15 (m, 2H);
Mass data (APCI, Pos.): m/z 454 (M + H)+.
実施例68:
N−{[1−(4−ビフェニリルスルホニル)−4−ピペリジニル]メチル]−4−クロロ−3−メトキシベンズアミド
1H NMR (DMSO-d6): d 8.57 (t, J = 5.3 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 7.8, 2H), 7.75 (d, J = 7.8 Hz, 2H), 7.58-7.37 (m, 6H), 3.89 (s, 3H), 3.67 (d, J = 11.5 Hz, 2H), 3.13 (t, J = 6.0 Hz, 2H), 2.29 (t, J = 11.3 Hz, 2H), 1.74 (d, J = 12.4 Hz, 2H), 1.58-1.49 (m, 1H), 1.23 (d, J = 9.4 Hz, 2H);
Mass data (APCI, Pos.): m/z 499 (M + H)+.
実施例69:
N−{[1−(3−ビフェニルイルスルホニル)−4−ピペリジニル]メチル]−4−クロロ−3−メトキシベンズアミド
1H NMR (DMSO-d6): d 8.61-8.52 (m, 1H), 8.07-7.51 (m, 12H), 3.90 (s, 3H), 3.78-3.64 (m, 2H), 3.19-3.07 (m, 2H), 2.34-2.25 (m, 2H), 1.82-1.70 (m, 2H), 1.55-1.51 (m, 1H), 1.29-1.21 (m, 2H);
Mass data (APCI, Pos.): m/z 499 (M + H)+.
実施例70:
4−クロロ−3−メトキシ−N−[(1−{[6−(4−モルホリニル)−3−ピリジニル]スルホニル}−4−ピペリジニル)メチル]ベンズアミド
1H NMR (DMSO-d6): d 8.57 (t, J = 5.5 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 7.75 (dd, J = 2.4, 9.1 Hz, 1H), 7.58-7.36 (m, 3H), 6.95 (d, J = 9.2 Hz, 1H), 3.91 (s, 3H), 3.63-3.53 (m, 8H), 3.36-3.23 (m, 2H), 3.13 (t, J = 6.0 Hz, 2H), 2.22 (t, J = 10.9 Hz, 2H), 1.80-1.65 (m, 3H), 1.31-1.03 (m, 2H);
Mass data (APCI, Pos.): m/z 509 (M + H)+.
実施例71:
4−クロロ−3−メトキシ−N−[(1−{[5−(2−ピリジニル)−2−チエニル]スルホニル}−4−ピペリジニル)メチル]ベンズアミド
1H NMR (DMSO-d6): d 8.63-8.54 (m, 2H), 8.13-7.35 (m, 8H), 3.89 (s, 3H), 3.72-3.59 (m, 2H), 3.55-3.41 (m, 2H), 3.21-3.09 (m, 2H), 1.85-1.55 (m, 3H), 1.31-1.22 (m, 2H);
Mass data (APCI, Pos.): m/z 506 (M + H)+.
実施例72:
N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1−(テトラヒドロ−2H−ピラン−2−イル)−5−(1−トリチル−1H−1,2,4−トリアゾール−3−イル)−1H−インダゾール−3−アミン
1H NMR (CDCl3): d 8.25 (s, 1H), 8.13-8.08 (m, 1H), 7.92 (s, 1H), 7.84-7.79 (m, 2H), 7.48-7.43 (m, 3H), 7.38-7.32 (m, 10H), 7.24-7.19 (m, 6H), 6.50 (s, 1H), 5.52-5.46 (m, 1H), 4.08-4.02 (m, 2H), 3.75-3.66 (m, 3H), 3.44-3.28 (m, 1H), 3.03-2.95 (m, 2H), 2.57-2.54 (m, 1H), 2.19-2.07 (m, 3H), 2.00-1.92 (m, 1H), 1.90-1.81 (m, 2H), 1.77-1.64 (m, 3H), 1.64-1.58 (m 1H), 1.49-1.36 (m, 2H);
Mass data (APCI, Pos.): m/z 781 (M + H)+.
実施例73:
N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−5−(1H−1,2,4−トリアゾール−3−イル)−1H−インダゾール−3−アミン
1H NMR (DMSO-d6): d 13.90 (s, 1H), 11.62 (s, 1H), 11.42 (s, 1H), 8.51-8.46 (m, 1H), 7.98-7.77 (m, 3H), 7.55-7.47 (m, 3H), 7.36-7.22 (m, 1H), 6.95 (s, 1H), 6.26-6.18 (m, 1H), 3.71 (s, 2H), 3.19-3.11 (m, 2H), 2.95-2.86 (m, 2H), 2.06 (t, J = 10.7 Hz, 2H), 1.84-1.76 (m, 2H), 1.75-1.64 (m, 1H), 1.35-1.20 (m, 2H);
Mass data (APCI, Pos.): m/z 455 (M + H)+.
実施例74:
(2E)−3−(2,3−ジクロロフェニル)アクリロイル アジド
1H NMR (CDCl3): d 8.16 (d, J = 15.9 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.28-7.22 (m, 1H), 6.41 (d, J = 15.9 Hz, 1H).
実施例75:
5,6−ジクロロ−1(2H)−イソキノリノン
1H NMR (CDCl3): d 11.66 (s, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.44-7.38 (m, 1H), 6.73 (d, J = 7.3 Hz).
実施例76:
tert−ブチル 4−[(5,6−ジクロロ−1−オキソ−2(1H)−イソキノリニル)メチル]−1−ピペリジンカルボキシレート
1H NMR (CDCl3): d 8.28 (d, J= 8.7 Hz, 1H), 7.53 (d, J= 8.7 Hz, 1H), 7.12 (d, J= 7.6 Hz, 1H), 6.86 (d, J= 7.6 Hz, 1H), 4.23-4.03 (m, 2H), 3.96-3.77 (m, 2H), 2.75-2.59 (m 2H), 2.15-2.05 (m, 1H), 1.72-1.59 (m, 2H), 1.48-1.40 (m, 11H);
Mass data (APCI, Pos.): m/z 311 (M - tert-butoxylcarbonyl + H) +.
実施例77:
5,6−ジクロロ−2−(4−ピペリジニルメチル)−1(2H)−イソキノリノン 塩酸塩
Mass data (ESI, Pos.): m/z 311 (M + H)+.
実施例78:
5,6−ジクロロ−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1(2H)−イソキノリノン
1H NMR (CDCl3): d 8.28 (d, J = 8.7 Hz, 1H), 7.82-7.76 (m, 2H), 7.52 (d, J = 8.7 Hz, 1H), 7.48-7.41 (m, 3H), 7.13 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 6.47 (s, 1H), 3.88 (d, J = 7.1 Hz, 2H), 3.72 (s, 2H), 3.01-2.94 (m, 2H), 2.16-2.06 (m, 2H), 1.98-1.87 (m, 1H), 1.74-1.66 (m, 2H), 1.50-1.38 (m, 2H);
Mass data (APCI, Pos.): m/z 468 (M + H)+.
実施例79:
6−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,6−ジヒドロ−7H−ピロロ[2,3−c]ピリジン−7−オン
1H NMR (CDCl3): d 9.96 (s, 1H), 7.84-7.76 (m, 2H), 7.49-7.41 (m, 3H), 7.25-7.21 (m, 1H), 6.85 (d, J = 7.1 Hz, 1H), 6.52 (d, J = 7.1 Hz, 1H), 6.78 (s, 1H), 6.39-6.35 (m, 1H), 3.93 (d, J = 7.2 Hz, 2H), 3.72 (s, 2H), 3.02-2.95 (m, 2H), 2.16-2.06 (m, 2H), 1.99-1.87 (m, 1H), 1.75-1.65 (m, 2H), 1.52-1.38 (m, 2H);
Mass data (APCI, Pos.): m/z 389 (M + H)+.
実施例80:
2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1(2H)−イソキノリノン
1H NMR (CDCl3): d 8.42 (d, J = 8.2 Hz, 1H), 7.81-7.78 (m, 2H), 7.65-7.61 (m, 1H), 7.51-7.43 (m, 5H), 7.00 (d, J = 7.7 Hz, 1H), 6.48-6.46 (m, 2H), 3.88 (d, J = 7.1 Hz, 2H), 3.71 (s, 2H), 2.99-2.94 (m, 2H), 2.14-2.07 (m, 2H), 2.00-1.90 (m, 1H), 1.74-1.69 (m, 2H), 1.49-1.39 (m, 2H).
Mass data (APCI, Pos.): m/z 400 (M + H)+.
実施例81:
4−クロロ−7−ヒドラジノ−3−フェニルイソオキサゾロ[4,5−d]ピリダジン
1H NMR (DMSO-d6): d 9.33 (br s, 1H), 7.80 (d, J = 7.0 Hz, 2H), 7.66-7.58 (m, 3H), 4.72 (br s, 2H);
Mass data (ESI, Pos.): m/z 262 (M + H)+.
実施例82:
4−クロロ−3−フェニルイソオキサゾロ[4,5−d]ピリダジン
1H NMR (CDCl3): d 9.71 (s, 1H), 7.83-7.80 (m, 2H), 7.67-7.57 (m, 3H).
Mass data (ESI, Pos.): m/z 232 (M + H)+.
実施例83:
tert−ブチル 4−{[(3−フェニルイソオキサゾロ[4,5−d]ピリダジン−4−イル)アミノ]メチル}−1−ピペリジンカルボキシレート
Mass data (ESI, Pos.): m/z 432 (M + Na)+.
実施例84:
3−フェニル−N−(4−ピペリジニルメチル)イソオキサゾロ[4,5−d]ピリダジン−4−アミン 塩酸塩
1H NMR (DMSO-d6): d 9.34 (s, 1H), 8.73 (br s, 1H), 8.54 (br s, 1H), 7.81-7.78 (m, 2H), 7.71-7.64 (m, 3H), 6.70 (br s, 1H), 3.49 (t, J = 6.7 Hz, 2H), 3.31-3.25 (m, 2H), 2.84 (br q, J = 11.7 Hz, 2H), 2.00 (m, 1 H), 1.90-1.83 (m, 2H), 1.45-1.34 (m, 2H);
Mass data (ESI, Pos.): m/z 310 (M + H)+.
実施例85:
3−フェニル−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)イソオキサゾロ[4,5−d]ピリダジン−4−アミン
1H NMR (CDCl3): d 9.14 (s, 1H), 7.82-7.80 (m, 2H), 7.72-7.70 (m, 2H), 7.66-7.61 (m, 3H), 7.48-7.44 (m, 3H), 6.49 (s, 1H), 4.97 (br t, J = 5.1 Hz, 1H), 3.73 (s, 2H), 3.58 (t, J = 5.9 Hz, 2H), 2.99-2.94 (m, 2H), 2.15-2.08 (m, 2H), 1.73-1.64 (m, 3H), 1.40-1.30 (m, 2H);
Mass data (APCI, Pos.): m/z 467 (M + H)+.
実施例86:
N−[(1−{[3−(4−クロロフェニル)−5−イソオキサゾリル]メチル]−4−ピペリジニル)メチル]−3−フェニルイソオキサゾロ[4,5−d]ピリダジン−4−アミン
1H NMR (CDCl3): d 9.14 (s, 1H), 7.76-7.69 (m, 4H), 7.67-7.61 (m, 3H), 7.45-7.42 (m, 2H), 6.46 (s, 1H), 4.97 (br t, J = 5.5 Hz, 1H), 3.72 (s, 2H), 3.58 (t, J = 6.3 Hz, 2H), 2.98-2.93 (m, 2H), 2.15-2.08 (m, 2H), 1.73-1.67 (m, 3H), 1.40-1.29 (m, 2H);
Mass data (ESI, Pos.): m/z 523 (M + Na)+.
実施例87:
N−[(1−{[3−(3−クロロフェニル)−5−イソオキサゾリル]メチル]−4−ピペリジニル)メチル]−3−フェニルイソオキサゾロ[4,5−d]ピリダジン−4−アミン
1H NMR (CDCl3): d 9.14 (s, 1H), 7.80 (m, 1H), 7.72-7.68 (m, 3H), 7.67-7.61 (m, 3H), 7.44-7.38 (m, 2H), 6.48 (s, 1H), 4.97 (br t, J = 5.1 Hz, 1H), 3.73 (s, 2H), 3.58 (t, J = 6.3 Hz, 2H), 2.98-2.93 (m, 2H), 2.15-2.08 (m, 2H), 1.73-1.65 (m, 3H), 1.40-1.30 (m, 2H);
Mass data (APCI, Pos.): m/z 501 (M + H)+.
実施例88:
N−[(1−{[3−(2−クロロフェニル)−5−イソオキサゾリル]メチル]−4−ピペリジニル)メチル]−3−フェニルイソオキサゾロ[4,5−d]ピリダジン−4−アミン
1H NMR (CDCl3): d 9.13 (s, 1H), 7.76-7.69 (m, 3H), 7.68-7.61 (m, 3H), 7.49 (m, 1H), 7.42-7.34 (m, 2H), 6.64 (s, 1H), 4.98 (br t, J = 5.5 Hz, 1H), 3.76 (s, 2H), 3.58 (t, J = 6.3 Hz, 2H), 3.00-2.95 (m, 2H), 2.16-2.09 (m, 2H), 1.74-1.66 (m, 3H), 1.41-1.30 (m, 2H);
Mass data (ESI, Pos.): m/z 523 (M + Na)+.
実施例89:
3−フェニル−4−(4−ピペリジニルメトキシ)イソオキサゾロ[4,5−d]ピリダジン
1H NMR (DMSO-d6): d 9.73 (s, 1H), 8.08-8.05 (m, 2H), 7.67-7.58 (m, 3H), 4.48 (d, J = 6.3 Hz, 2H), 2.97-2.92 (m, 2H), 2.51-2.43 (m, 2H), 2.15 (br s, 1H), 1.91 (m, 1H), 1.67-1.61 (m, 2H), 1.24-1.13 (m, 2H);
Mass data (ESI, Pos.): m/z 311 (M + H)+.
実施例90:
4−[(1−{[3−(2−クロロフェニル)−5−イソオキサゾリル]メチル}−4−ピペリジニル)メトキシ]−3−フェニルイソオキサゾロ[4,5−d]ピリダジン
1H NMR (DMSO-d6): d 9.74 (s, 1H), 8.07-8.03 (m, 2H), 7.74-7.47 (m, 7H), 6.83 (s, 1H), 4.54-4.49 (m, 2H), 3.78 (br s, 2H), 3.00-2.87 (m, 2H), 2.18-2.06 (m, 2H), 1.91-1.68 (m, 3H), 1.49-1.36 (m, 2H);
Mass data (ESI, Pos.): m/z 502 (M + H)+.
実施例91:
3−フェニル−4−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メトキシ)イソオキサゾロ[4,5−d]ピリダジン
1H NMR (CDCl3): d 9.40 (s, 1H), 8.09-8.06 (m, 2H), 7.83-7.80 (m, 2H), 7.60-7.51 (m, 3H), 7.49-7.42 (m, 3H), 6.50 (s, 1H), 4.61 (d, J = 6.3 Hz, 2H), 3.76 (s, 2H), 3.03-2.99 (m, 2H), 2.22-2.15 (m, 2H), 1.93 (m, 1H), 1.85-1.79 (m, 2H), 1.56-1.46 (m, 2H);
Mass data (ESI, Pos.): m/z 468 (M + H)+.
実施例92:
4−アニリノ−2−(メチルチオ)−5−ピリミジンカルボン酸
1H NMR (DMSO-d6): d 10.62 (br s, 1H), 8.70 (s, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.14 (t, J = 7.8 Hz, 1H), 2.51 (s, 3H);
Mass data (APCI, Pos.): m/z 262 (M + H)+.
実施例93:
4−アニリノ−2−(メチルチオ)−5−ピリミジンカルボキサアミド
1H NMR (DMSO-d6): d 11.51 (s, 1H), 8.72 (s, 1H), 8.29 (s, 1H), 7.74 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 2H), 7.11 (t, J = 8.0 Hz, 1H), 2.49 (s, 3H).
Mass data (APCI, Pos.): m/z 261 (M + H)+.
実施例94:
4−アニリノ−2−[({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)アミノ]−5−ピリミジンカルボキサアミド
1H NMR (CDCl3): d 11.04 (s, 1H), 8.25 (s, 1H), 7.81-7.78 (m, 2H), 7.72-7.64 (m, 2H), 7.45-7.43 (m, 3H), 7.30 (t, J = 7.5 Hz, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.48 (s, 1H), 5.56-5.46 (m, 3H), 3.72 (s, 2H), 3.36-3.33 (m, 2H), 2.99-2.96 (m, 2H), 2.15-2.08 (m, 2H), 1.80-1.77 (m, 2H), 1.73-1.64 (m, 1H), 1.43-1.33 (m, 2H);
Mass data (APCI, Pos.): m/z 484 (M + H)+.
実施例95:
メチル 6−ブロモ−3−ヒドロキシ−1−オキソ−4−フェニル−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,2,3,4−テトラヒドロ−3−イソキノリンカルボキシレート
1H NMR (CDCl3): d 8.05 (d, J = 8.4 Hz, 1H), 7.83-7.77 (m, 2H), 7.56-7.51 (m, 1H), 7.48-7.42 (m, 3H), 7.40-7.33 (m, 3H), 7.23-7.18 (m, 2H), 7.10 (s, 1H), 6.46 (s, 1H), 4.73 (s, 1H), 3.74 (s, 3H), 3.67 (s, 2H), 3.62-3.58 (m, 2H), 2.97-2.89 (m, 1H), 2.86-2.78 (m, 1H), 2.04-1.91 (m, 2H), 1.74-1.91 (m, 1H), 1.40-1.30 (m, 2H), 1.24-1.16 (m, 2H).
実施例96:
メチル 6−ブロモ−1−オキソ−4−フェニル−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,2−ジヒドロ−3−イソキノリンカルボキシレート
1H NMR (CDCl3): d 8.34 (d, J = 8.6 Hz, 1H), 7.82-7.76 (m, 2H), 7.66-7.60 (m, 1H), 7.48-7.41 (m, 6H), 7.36-7.32 (m, 1H), 7.31-7.27 (m, 2H), 6.46 (s, 1H), 4.03-3.94 (m, 2H), 3.71 (s, 2H), 3.50 (s, 3H), 2.99-2.91 (m, 2H), 2.14-2.05 (m, 2H), 1.96-1.85 (m, 1H), 1.72-1.62 (m, 2H), 1.48-1.35 (m, 2H);
Mass data (APCI, Pos.): m/z 612 (M + H)+.
実施例97:
メチル 1−オキソ−4−フェニル−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,2−ジヒドロ−3−イソキノリンカルボキシレート
1H NMR (CDCl3): d 8.50 (d, J = 7.2 Hz, 1H) 7.85-7.75 (m, 2H), 7.61-7.50 (m, 2H), 7.49-7.37 (m, 6H), 7.34-7.30 (m, 2H), 7.23-7.19 (m, 1H), 6.47 (s, 1H), 4.08-3.96 (m, 2H), 3.70 (s, 2H), 3.45 (s, 3H), 3.00-2.90 (m, 2H), 2.16-2.05 (m 2H), 2.00-1.86 (m, 1H), 1.75-1.63 (m, 2H), 1.51-1.35 (m, 2H);
Mass data (APCI, Pos.): m/z 534 (M + H)+.
実施例98:
メチル 6−クロロ−1−オキソ−4−フェニル−2−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,2−ジヒドロ−3−イソキノリンカルボキシレート
1H NMR (CDCl3): d 8.42 (d, J = 8.6 Hz, 1H), 7.81-7.75 (m, 2H), 7.50-7.41 (m, 7H), 7.31-7.27 (m, 2H), 7.19-7.16 (m, 1H), 6.47 (s, 1H), 4.03-3.95 (m, 2H), 3.71 (s, 2H), 3.45 (s, 3H), 3.00-2.91 (m, 2H), 2.15-2.05 (m, 2H), 1.98-1.85 (m, 1H), 1.73-1.61 (m, 2H), 1.49-1.37 (m, 2H);
Mass data (APCI, Pos.): m/z 568 (M + H)+.
実施例101:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−フェニルチアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
濃縮して、シリカゲルのカラムクロマトグラフィー(展開溶媒:50−100% 酢酸エチル/ヘキサン (0.5% トリエチルアミン))で精製することで、以下の物性値を有する標題化合物(0.044 g)を得た。
1H NMR (CDCl3): d 7.94-7.90 (m, 2H), 7.83-7.77 (m, 1H), 7.61 (s, 1H), 7.44-7.40 (m, 3H), 7.19 (s, 1H), 5.10 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.01-2.93 (m, 2H), 2.10-2.00 (m, 2H), 1.77-1.68 (m, 2H), 1.67-1.57 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.41-1.31 (m, 2H);
Mass data (APCI, Pos.): m/z 477 (M + H)+.
実施例102:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((4−メチル−2−フェニルチアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 7.91-7.87 (m, 2H), 7.83- 7.77 (m, 1H), 7.44-7.36 (m, 3H), 7.18 (s, 1H), 5.09 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.64 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.01-2.93 (m, 2H), 2.41 (s, 3H), 2.09-2.00 (m, 2H), 1.76-1.68 (m, 2H), 1.66-1.60 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.40-1.31 (m, 2H);
Mass data (APCI, Pos.): m/z 491 (M + H)+.
実施例103:
4−アミノ−5−シアノ−N−((1−((4−((ジメチルアミノ)メチル)−2−フェニルチアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミド
1H NMR (CDCl3): d 7.95-7.91 (m, 2H), 7.83-7.78 (m, 1H), 7.42-7.37 (m, 3H), 7.19 (s, 1H), 5.10 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.73 (s, 2H), 3.57 (s, 2H), 3.35 (t, J = 6.55 Hz, 2H), 3.02-2.95 (m, 2H), 2.30 (s, 6H), 2.10-2.00 (M, 2H), 1.76-1.69 (m, 2H), 1.68-1.58 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.41-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 534 (M + H)+.
実施例104:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((3−(ピリジン−2−イル)イソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.68 (d, J = 4.3 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.82-7.76 (m, 2H), 7.37-7.32 (m, 1H), 7.18 (s, 1H), 6.81 (s, 1H), 5.08 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.02-2.95 (m, 2H), 2.19-2.10 (m, 2H), 1.77-1.70 (m, 2H), 1.63-1.57 (m, 1H), 1.48-1.33 (m, 5H);
Mass data (APCI, Pos.): m/z 462 (M + H)+.
実施例105:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−フェニル−1H−イミダゾール−4−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3) d 9.52 (s, 1H), 9.30 (s, 1H), 7.86-7.77 (m, 3H), 7.48-7.31 (m, 3H), 7.19 (s, 1H), 6.98 (s, 1H), 5.14 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.61-3.52 (m, 2H), 3.38-3.29 (m, 2H), 3.11-2.88 (m, 2H), 2.09-1.93 (m, 2H), 1.78-1.55 (m, 3H), 1.43- (t, J = 7.1 Hz, 3H), 1.38-1.28 (m, 2H);
Mass data (APCI, Pos.): m/z 460 (M + H)+.
実施例106:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((1−メチル−2−フェニル−1H−イミダゾール−4−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 7.84-7.79 (m, 1H), 7.63-7.57 (m, 2H), 7.48-7.36 (m, 3H), 7.24 (s, 1H), 6.88 (s, 1H), 5.36 (s, 2H), 4.424 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 3.54 (s, 2H), 3.33 (t, J = 6.5 Hz, 2H), 3.14-3.02 (m, 2H), 2.14-2.01 (m, 2H), 1.77-1.67 (m, 2H), 1.65-1.54 (m, 1H), 1.48-1.32 (m, 5H);
Mass data (APCI, Pos.): m/z 474 (M + H).
実施例107:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((1−メチル−2−フェニル−1H−イミダゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 7.85-7.77 (m, 1H), 7.65-7.58 (m, 2H), 7.50-7.35 (m, 3H), 7.23 (s, 1H), 6.96 (s, 1H), 5.27 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H), 3.47 (s, 2H), 3.33 (t, J = 6.6 Hz, 2H), 2.98-2.89 (m, 2H), 2.02-1.91 (m, 2H), 1.77-1.67 (m, 2H), 1.66-1.56 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.36-1.23 (m, 2H);
Mass data (APCI, Pos.): m/z 474 (M + H).
実施例108:
tert−ブチル 2−(5−((4−((4−アミノ−5−シアノ−6−エトキシピコリンアミド)メチル)ピペリジン−1−イル)メチル)−3−フェニル−1H−ピラゾール−1−イル)エチルカルバメート
1H NMR (CDCl3): d 7.85-7.74 (m, 3H), 7.38 (t, J = 7.5 Hz, 2H), 7.32-7.28 (m, 1H), 7.19 (s, 1H), 6.42 (s, 1H), 5.57 (s, 1H), 5.12 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.33-4.26 (m, 2H), 3.66-3.58 (m, 2H), 3.48 (s, 2H), 3.37-3.29 (m, 2H), 2.98-2.90 (m, 2H), 2.07-1.98 (m, 2H), 1.77-1.67 (m, 2H), 1.67-1.59 (m, 1H), 1.47-1.31 (m, 14H);
Mass data (APCI, Pos.): m/z 603 (M + H)+.
実施例109:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((5−(ピリジン−2−イル)−1,3,4−チアジアゾール−2−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.65 (d, J = 3.1 Hz, 1H), 8.33 (d, J = 7.8 Hz, 1H), 7.87-7.80 (m, 2H), 7.40-7.37 (m, 1H), 7.23 (s, 1H), 5.21 (s, 2H), 4.44 (q, J = 7.0 Hz, 2H), 3.98 (s, 2H), 3.35 (t, J = 6.3 Hz, 2H), 3.01 (bd, J = 11.0, 2H), 2.23 (t, J = 11.7 Hz, 2H), 1.74 (bd, J = 12.5 Hz, 2H), 1.68-1.62 (m, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.42-1.35 (m, 2H).
Mass data (ESI, Pos.): m/z 501 (M + Na)+.
実施例110:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(ピリミジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.83 (d, J = 5.5 Hz, 2H), 7.81-7.79 (m, 2H), 7.29 (t, J = 4.7 Hz, 1H), 7.19 (s, 1H), 5.12 (s, 2H), 4.44 (q, J = 7.0 Hz, 2H), 3.79 (s, 2H), 3.34 (t, J = 7.0 Hz, 2H), 2.97 (d, J = 11.7 Hz, 2H), 2.11-2.05 (m, 2H), 1.72 (d, J = 11.7 Hz, 2H), 1.67-1.57 (m, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.42-1.32 (m, 2H);
Mass data (ESI, Pos.): m/z 501 (M + Na)+.
実施例111:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(4−フルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): d 8.45 (t, J = 6.3 Hz, 1H), 7.97-7.94 (m, 2H), 7.71 (s, 1H), 7.35-7.26 (m, 4H), 7.03 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.71 (s, 2H), 3.16 (t, J = 5.5 Hz, 2H), 2.86 (d, J = 11 Hz, 2H), 1.96 (t, J = 11.7 Hz, 2H), 1.62-1.51 (m, 3H), 1.31 (t, J = 7.0 Hz, 3H), 1.23-1.13 (m, 2H);
Mass data (ESI, Pos.): m/z 517 (M + Na)+.
実施例112:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(3−フルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): d 8.45 (t, J = 6.3 Hz, 1H), 7.76 (s, 1H), 7.74-7.69 (m, 2H), 7.57-7.51 (m, 1H), 7.34-7.29 (m, 3H), 7.03 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.73 (s, 2H), 3.16 (t, J = 5.5 Hz, 2H), 2.86 (d, J = 11.0 Hz, 2H), 1.96 (t, J = 11.7 Hz, 2H), 1.62-1.51 (m, 3H), 1.31 (t, J = 7.0 Hz, 3H), 1.23-1.13 (m, 2H);
Mass data (ESI, Pos.): m/z 517 (M + Na)+.
実施例113:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(2−フルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): d 8.45 (t, J = 5.5 Hz, 1H), 8.20 (t, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.55-7.50 (m, 1H), 7.44-7.25 (m, 4H), 7.03 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.77 (s, 2H), 3.16 (t, J = 5.5 Hz, 2H), 2.86 (d, J = 11.0 Hz, 2H), 1.96 (t, J = 11.7 Hz, 2H), 1.63-1.51 (m, 3H), 1.31 (t, J = 7.0 Hz, 3H), 1.23-1.14 (m, 2H);
Mass data (ESI, Pos.): m/z 517 (M + Na)+.
実施例114:
4−アミノ−5−シアノ−N−((1−((2−(3,5−ジフルオロピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミド
1H NMR (DMSO-d6): d 8.16 (d, J = 2.3 Hz, 1H), 8.45 (t, J = 6.3 Hz, 1H), 8.14 (dt, J = 8.6, 2.3 Hz, 1H), 7.83 (s, 1H), 7.29 (bs, 1H), 7.03 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.75 (s, 2H), 3.16 (t, J = 6.2 Hz, 2H), 2.86 (d, J = 11.0 Hz, 2H), 1.97 (t, J = 11.7 Hz, 2H), 1.63-1.51 (m, 3H), 1.31 (t, J = 7.0 Hz, 3H), 1.23-1.14 (m, 2H);
Mass data (APCI, Pos.): m/z 514 (M + Na)+.
実施例115:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.63-8.56 (m, 1H), 8.20-8.11 (m, 1H), 7.85-7.75 (m, 2H), 7.67 (s, 1H), 7.33-7.28 (m, 1H), 7.19 (s, 1H), 5.12 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.78 (s, 2H), 3.30 (t, J = 6.5 Hz, 2H), 3.01-2.93 (m, 2H), 2.12-2.02 (m, 2H), 1.76-1.72 (m, 2H), 1.66-1.53 (obs, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.41-1.33 (m, 2H);
Mass data (ESI, Pos.): m/z 478 (M + H)+.
実施例116:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−フェニルオキサゾール−4−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): d 8.45 (t, J = 6.2 Hz, 1H), 8.03 (br, 1H), 7.97-7.95 (m, 2H), 7.53-7.52 (m 2H), 7.30 (br, 2H), 7.03 (s, 1H), 5.76 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.42 (br, 2H), 3.18-3.14 (m, 2H), 2.89 (d, J = 10.5 Hz, 2H), 1.96 (d, J = 10.5 Hz, 2H), 1.62-1.55 (m, 3H), 1.31 (t, J = 7.0, 3H), 1.24-1.15 (m, 2H);
Mass data (APCI, Pos.): m/z 461 (M + H)+.
実施例117:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((5−フェニルオキサゾール−2−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
Mass data (APCI, Pos.): m/z 461 (M + H)+.
実施例118:
4−アミノ−5−シアノ−N−((1−((4−((ジメチルアミノ)メチル)−2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミド
1H NMR (CDCl3): d 8.63-8.54(m, 1H), 8.19-8.10 (m, 1H), 8.09-8.02 (m, 1H), 7.88-7.77 (m, 1H), 7.41-7.32 (m, 1H), 7.09 (s, 1H), 4.82 (s, 2H), 4.43 (q, J = 6.9, 2H), 4.24-4.14 (m, 2H), 3.96-3.86 (m, 2H), 3.43-3.32 (m, 2H), 3.17-3.07 (m, 2H), 2.74 (s, 2H), 2.50 (s, 6H), 2.36-2.24 (m 2H), 1.89-1.68 (m, 2H), 1.43 (t, J = 6.9, 3H), 1.39-1.26 (m, 1H);
Mass data (ESI, Pos.): m/z 535 (M + H)+.
実施例119:
4−アミノ−N−((1−((1−(2−アミノエチル)−3−フェニル−1H−ピラゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): d 7.84-7.75 (m, 3H), 7.38 (t, J = 7.6 Hz, 2H), 7.31-7.27 (m, 1H), 7.18 (s, 1H), 6.43 (s, 1H), 5.14 (s, 2H), 4.47-4.38 (m, 3H), 4.26 (t, J = 5.8 Hz, 1H), 3.88-3.81 (m, 1H), 3.51 (s, 2H), 3.36-3.29 (m, 2H), 3.25-3.18 (m, 1H), 2.98-2.87 (m, 2H), 2.02-1.93 (m, 2H), 1.76-1.66 (m, 2H), 1.65-1.57 (m, 1H), 1.43 (t, J = 7.1 Hz, 3H), 1.35-1.26 (m, 2H);
Mass data (APCI, Pos.): m/z 503 (M + H)+.
実施例120:
メチル 3−フェニル−1H−ピラゾール−5−カルボキシレート 塩酸塩
1H NMR (DMSO-d6): d 7.93-7.78 (m, 2H), 7.54-7.17 (m, 4H), 3.85 (s, 3H);
Mass data (APCI, Pos.): m/z 203 (M + H (free base))+.
実施例121:
メチル 1−(2−(tert−ブトキシカルボニルアミノ)エチル)−3−フェニル−1H−ピラゾール−5−カルボキシレート
1H NMR (CDCl3): d 7.80 (d, J = 7.8 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.14 (s, 1H), 4.95 (s, 1H), 4.72 (t, J = 4.0 Hz 2H), 3.91 (s, 3H), 3.69-3.59 (m, 2H), 1.40 (s, 9H);
Mass data (APCI, Pos.): m/z 346 (M + H)+.
実施例122:
tert−ブチル 2−(5−(ヒドロキシメチル)−3−フェニル−1H−ピラゾール−1−イル)エチルカルバメート
1H NMR (DMSO-d6): d 7.76 (d, J = 7.1 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 6.96-6.90 (m, 1H), 6.60 (s, 1H), 5.33 (t, J = 5.4 Hz, 1H), 4.51 (d, J = 5.4 Hz, 2H), 4.16 (t, J = 6.6 Hz, 2H), 1.36 (s, 9H);
Mass data (APCI, Pos.): m/z 318 (M + H)+.
実施例123:
tert−ブチル 2−(5−ホルミル−3−フェニル−1H−ピラゾール−1−イル)エチルカルバメート
1H NMR (CDCl3): d 9.90 (s, 1H), 7.82 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.19 (s, 1H), 4.85 (s, 1H), 4.69 (t, J = 6 Hz, 2H), 3.67-3.59 (m, 2H), 1.39 (s, 9H);
Mass data (APCI, Pos.): m/z 316 (M + H)+.
実施例124:
(3−(ピリジン−2−イル)イソオキサゾール−5−イル)メタノール
1H NMR (DMSO-d6): d 8.72 (d, J = 4.8 Hz, 1H), 8.0 (d, J = 7.7 Hz, 1H), 7.96 (td, J = 1.7, 7.7 Hz, 1H), 7.53-7.50 (m, 1H), 6.88 (s, 1H), 5.72 (t, J = 6.1 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H);
Mass data (APCI, Pos.): m/z 177 (M + H)+.
実施例125:
3−(ピリジン−2−イル)イソオキサゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.05 (s, 1H), 8.72 (d, J = 4.7 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.85 (dt, J = 7.8, 1.6 Hz, 1H), 7.65 (s, 1H), 7.43-7.40 (m, 1H).
実施例126:
エチル 4−(ブロモメチル)−2−フェニルチアゾール−5−カルボキシレート
1H NMR (CDCl3): d 8.01-7.97 (m, 2H), 7.51-7.44 (m, 3H), 4.99 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H);
Mass data (APCI, Pos.): m/z 328 (M + H)+.
実施例127:
エチル 4−((ジメチルアミノ)メチル)−2−フェニルチアゾール−5−カルボキシレート
1H NMR (DMSO-d6): d 8.04-7.99 (m, 2H), 7.57-7.52 (m, 3H), 4.32 (q, J = 7.1 Hz, 2H), 3.93 (s, 2H), 2.25 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H);
Mass data (APCI, Pos.): m/z 291 (M + H)+.
実施例128:
(4−((ジメチルアミノ)メチル)−2−フェニルチアゾール−5−イル)メタノール
Mass data (APCI, Pos.): m/z 249 (M + H)+.
実施例129:
4−((ジメチルアミノ)メチル)−2−フェニルチアゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.38 (s, 1H), 8.04-8.00 (m, 2H), 7.52-7.43 (m, 3H), 3.95 (s, 2H), 2.37 (s, 6H);
Mass data (APCI, Pos.): m/z 247 (M + H)+.
実施例130:
メチル 2−フェニル−1H−イミダゾール−4−カルボキシレート
1H NMR (CDCl3): d 10.41-10.11 (m, 1H), 7.98-7.86 (m, 2H), 7.84-7.77 (m, 1H), 7.52-7.36 (m, 3H), 3.92 (s, 3H);
Mass data (APCI, Pos.): m/z 203 (M + H)+.
実施例131:
(2−フェニル−1H−イミダゾール−4−イル)メタノール
1H NMR (CDCl3): d 7.85-7.79 (m, 2H), 7.48-7.35 (m, 3H), 7.07 (s, 1H), 4.71 (s, 2H);
Mass data (APCI, Pos.): m/z 175 (M + H)+.
実施例132:
2−フェニル−1H−イミダゾール−4−カルバアルデヒド
1H NMR (CDCl3): d 10.25 (s, 1H), 9.74 (s, 1H), 7.99-7.81 (m, 3H), 7.54-7.45 (m, 3);
Mass data (APCI, Pos.): m/z 173 (M + H)+.
実施例133:
メチル 1−メチル−2−フェニル−1H−イミダゾール−4−カルボキシレート
1H NMR (CDCl3): d 7.69 (s, 1H), 7.67-7.63 (m, 2H), 7.48-7.44 (m, 3H), 3.91 (s, 3H), 3.78 (s, 3H);
Mass data (APCI, Pos.): m/z 217 (M + H)+.
実施例134:
(1−メチル−2−フェニル−1H−イミダゾール−4−イル)メタノール
Mass data (APCI, Pos.): m/z 189 (M + H)+.
実施例135:
1−メチル−2−フェニル−1H−イミダゾール−4−カルバアルデヒド
Mass data (APCI, Pos.): m/z 187 (M + H)+.
実施例136:
メチル 1−メチル−2−フェニル−1H−イミダゾール−5−カルボキシレート
1H NMR (CDCl3): d 7.84 (s, 1H), 7.65-7.60 (m, 2H), 7.52-7.46 (m, 3H), 3.96 (s, 3H), 3.88 (s, 3H);
Mass data (APCI, Pos.): m/z 217 (M + H)+.
実施例137:
(1−メチル−2−フェニル−1H−イミダゾール−5−イル)メタノール
Mass data (APCI, Pos.): m/z 189 (M + H)+.
実施例138:
1−メチル−2−フェニル−1H−イミダゾール−5−カルバアルデヒド
Mass data (APCI, Pos.): m/z 187 (M + H)+.
実施例139:
2−(ピリジン−2−イル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.09 (s, 1H), 8.68 (d, J = 4.7 Hz, 1H), 8.48 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.86 (dt, J = 7.8, 1.6 Hz, 1H), 7.44-7.41 (m, 1H).
実施例140:
2−(ピリミジン−2−イル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.14 (s, 1H), 8.92 (d, J = 4.7 Hz, 2H), 8.61 (s, 1H), 7.42 (t, J = 4.7 Hz, 1H).
実施例141:
2−(3,5−ジフルオロピリジン−2−イル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.12 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 2.3 Hz, 1H), 7.42 (dt, J = 7.8, 2.3 Hz, 1H).
実施例142:
2−(4−フルオロフェニル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.05 (s, 1H), 8.42 (s, 1H), 8.06-8.02 (m, 2H), 7.21-7.16 (m, 2H).
実施例143:
2−(3−フルオロフェニル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.07 (s, 1H), 8.45 (s, 1H), 7.80-7.76 (m, 2H), 7.50-7.45 (m, 1H), 7.25-7.20 (m, 1H).
実施例144:
2−(2−フルオロフェニル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.11 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 8.37 (dt, J = 7.8, 2.3 Hz, 1H), 7.54-7.48 (m, 1H), 7.34-7.23 (m, 2H).
実施例145:
3,5−ジフルオロピリジン−2−カルボチオアミド
1H NMR (DMSO-d6): d 10.26 (bs, 1H), 9.80 (bs, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.03 (dt, J = 10.2, 2.3 Hz, 1H).
実施例146:
N’−(2−(ベンジルオキシ)アセチル)ピコリノヒドラジド
1H NMR (CDCl3): d 10.08 (d, J = 5.5 Hz, 1H), 8.95 (d, J = 5.5 Hz, 1H), 8.58 (d, J = 3.9 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), (dt, J = 7.8, 1.6 Hz, 1H), 7.49-7.46 (m, 1H), 7.41-7.33 (m, 5H), 4.66 (s, 2H), 4.18 (s, 2H);
Mass data (APCI, Pos.): m/z 286 (M + H)+.
実施例147:
2−(ベンジルオキシメチル)−5−(ピリジン−2−イル)−1,3,4−チアジアゾール
1H NMR (CDCl3): d 8.66 (d, J = 5.5 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.88-7.84 (m, 1H), 7.41-7.30 (m, 6H), 4.99 (s, 2H), 4.69 (s, 2H);
Mass data (APCI, Pos.): m/z 284 (M + H)+.
実施例148:
(5−(ピリジン−2−イル)−1,3,4−チアジアゾール−2−イル)メタノール
1H NMR (CD3OD): d 8.66 (d, J = 4.7 Hz, 1H), 8.28 (d, J = 7.8 Hz, 1H), 7.98 (dt, J = 7.8, 1.6 Hz, 1H), 7.53-7.50 (m, 1H), 4.99 (s, 2H);
Mass data (APCI, Pos.): m/z 194 (M + H)+.
実施例149:
5−(ピリジン−2−イル)−1,3,4−チアジアゾール−2−カルバアルデヒド
1H NMR (CDCl3): d 10.26 (s, 1H), 8.70 (d, J = 4.7 Hz, 1H), 8.45 (d, J = 7.8 Hz, 1H), 7.92 (dt, J = 7.8, 1.6 Hz, 1H), 7.50-7.46 (m, 1H).
実施例150:
5−フェニルオキサゾール−2−カルバアルデヒド
1H NMR (DMSO-d6): d 9.72 (s, 1H), 8.12 (s, 1H), 7.88 (d, J = 7.02 Hz, 1H), 7.60-7.49 (m, 4H);
Mass data (APCI, Pos.): m/z 174 (M + H)+.
実施例151:
メチル 4−メチル−2−(ピリジン−2−イル)チアゾール−5−カルボキシレート
1H NMR (CDCl3): d 8.68-8.58 (m, 1H), 8.27-8.17 (m, 1H), 7.87-7.77 (m, 1H), 7.41-7.33 (m, 1H), 3.90 (s, 3H), 2.80 (s, 3H);
Mass data (ESI, Pos.): m/z 235 (M + H)+.
実施例152:
メチル 4−(ブロモメチル)−2−(ピリジン−2−イル)チアゾール−5−カルボキシレート
Mass data (ESI, Pos.): m/z 314 (M + H)+.
実施例153:
メチル 4−((ジメチルアミノ)メチル)−2−(ピリジン−2−イル)チアゾール−5−カルボキシレート
1H NMR (CDCl3): d 8.63-8.59 (m, 1H), 8.34-8.25 (m, 1H), 7.84-7.76 (m, 1H), 7.40-7.33 (m, 1H), 4.01 (s, 2H), 3.91 (m, 3H), 2.41 (s, 6H);
Mass data (ESI, Pos.): m/z 340 (M + H)+.
実施例154:
メチル 4−((4−(tert−ブトキシカルボニル)ピペラジン−1−イル)メチル)−2−(ピリジン−2−イル)チアゾール−5−カルボキシレート
Mass data (ESI, Pos.): m/z 419 (M + H)+.
実施例155:
(4−((ジメチルアミノ)メチル)−2−(ピリジン−2−イル)チアゾール−5−イル)メタノール
1H NMR (CDCl3): d 8.64-8.53 (m, 1H), 8.16-8.07 (m, 1H), 7.82-7.70 (m, 1H), 7.35-7.25 (m, 1H), 4.79 (s, 2H), 3.76 (m, 2H), 2.32 (s, 6H);
Mass data (ESI, Pos.): m/z 250 (M + H)+.
実施例156:
tert−ブチル 4−((5−(ヒドロキシメチル)−2−(ピリジン−2−イル)チアゾール−4−イル)メチル)ピペラジン−1−カルボキシレート
1H NMR (CDCl3): d 8.64-8.57 (m, 1H), 8.13-8.07 (m, 1H), 7.82-7.73 (m, 1H), 7.33-7.25 (m, 1H), 4.82 (s, 2H), 3.84 (m, 2H), 3.53-3.34 (m, 4H), 2.60-2.44 (m, 4H), 1.45 (s, 9H);
Mass data (ESI, Pos.): m/z 391 (M + H)+.
実施例157:
4−((ジメチルアミノ)メチル)−2−(ピリジン−2−イル)チアゾール−5−カルバアルデヒド
Mass data (ESI, Pos.): m/z 248 (M + H)+.
実施例158:
tert−ブチル 4−((5−ホルミル−2−(ピリジン−2−イル)チアゾール−4−イル)メチル)ピペラジン−1−カルボキシレート
1H NMR (CDCl3): d 10.44 (s, 1H), 8.68-8.63 (s, 1H), 8.28-8.20 (s, 1H), 7.88-7.78 (s, 1H), 7.44-7.35 (s, 1H), 4.04 (s, 2H), 3.50-3.42 (m, 4H), 2.61-2.51 (m, 4H), 1.45 (s, 9H);
Mass data (ESI, Pos.): m/z 389 (M + H)+.
実施例159:
tert−ブチル 4−((5−((4−((4−アミノ−5−シアノ−6−エトキシピコリンアミド)メチル)ピペリジン−1−イル)メチル)−2−(ピリジン−2−イル)チアゾール−4−イル)メチル)ピペラジン−1−カルボキシレート
1H NMR (CDCl3): d 8.62-8.53 (m, 1H), 8.19-8.14 (m, 1H), 7.85-7.72 (m, 2H), 7.33-7.26 (m, 1H), 7.19 (s, 1H), 5.14 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 3.72 (s, 2H), 3.69 (s, 2H), 3.53-3.38 (m, 8H), 3.37-3.29 (m, 2H), 3.01-2.92 (m, 2H), 2.58-2.42 (m, 3H), 2.08 (m, 2H), 1.75-1.58 (m, 2H), 1.45 (s, 9H), 1.41-1.26 (m, 3H);
Mass data (ESI, Pos.): m/z 676 (M + H)+.
実施例160:
4−アミノ−5−シアノ−6−エトキシ−N−[(1−{[4−(1−ピペラジニルメチル)−2−(2−ピリジニル)−1,3−チアゾール−5−イル]メチル]−4−ピペリジニル)メチル]−2−ピリジンカルボキサアミド トリス(トリフルオロアセテート)
1H NMR (DMSO-d6): d 8.73-8.56 (m, 2H), 8.16-8.10 (m, 1H), 8.04-7.95 (m, 1H), 7.59-7.53 (m, 1H), 7.38-7.29 (m, 1H), 7.04 (s, 1H), 4.69 (s, 2H), 4.48(q, J = 7.1 Hz, 2H), 3.99-3.92 (m, 2H), 3.52-3.42 (m, 2H), 3.28-2.99 (m, 9H), 2.90-2.79 (m, 4H), 1.90-1.80 (m, 3H), 1.52-1.37 (m 2H), 1.32 (t, J = 7.1 Hz, 3H);
Mass data (ESI, Pos.): m/z 576 (M + H)+.
実施例161:
4−アミノ−5−シアノ−6−モルホリノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.87-7.83 (m, 1H), 7.78-7.76 (m, 1H), 7.67 (s, 1H), 7.32-7.29 (m, 1H), 7.09 (s, 1H), 5.14 (s, 2H), 3.86-3.84 (m, 4H), 3.78 (s, 2H), 3.63-3.60 (m, 4H), 3.33 (t, J = 6.5 Hz, 2H), 3.01-2.94 (m, 2H), 2.09-2.07 (m, 2H), 1.72-1.70 (m, 2H), 1.62-1.56 (m, 1H), 1.42-1.31 (m, 2H);
Mass data (APCI, Pos.): m/z 519 (M + H)+.
実施例162:
4−アミノ−5−シアノ−6−(ピペラジン−1−イル)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.91-7.88 (m, 1H), 7.80-7.77 (m, 1H), 7.67 (s, 1H), 7.32-7.29 (m, 1H), 7.04 (s, 1H), 5.10 (s, 2H), 3.77 (s, 2H), 3.63-3.59 (m, 4H), 3.33 (t, J = 6.5 Hz, 2H), 3.04-3.03 (m, 2H), 2.97-2.95 (m, 2H), 2.08-2.03 (m, 2H), 1.82 (br s, 1H) 1.73-1.70 (m, 2H), 1.64-1.54 (m, 1H), 1.41-1.32 (m, 2H), 1.28-1.24 (m, 2H);
Mass data (APCI, Pos.): m/z 518 (M + H)+.
実施例163:
4−アミノ−5−シアノ−6−(4−メチルピペラジン−1−イル)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.91-7.87 (m, 1H), 7.80-7.76 (m, 1H), 7.67 (s, 1H), 7.31-7.28 (m, 1H), 7.07 (s, 1H), 5.16 (s, 2H), 3.78 (s, 2H), 3.67-3.65 (m, 4H), 3.34-3.31 (m, 2H), 2.98-2.95 (m, 2H), 2.58-2.56 (m, 4H), 2.35 (s, 3H), 2.09-2.05, (m, 2H), 1.73-1.70 (m, 2H), 1.64-1.54 (m, 1H), 1.41-1.31 (m, 2H);
Mass data (APCI, Pos.): m/z 532 (M + H)+.
実施例164:
4−アミノ−5−シアノ−6−(シクロプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.20-8.17 (m, 1H), 8.15-8.13 (m, 1H), 7.67 (s, 1H), 7.31-7.28 (m, 1H), 6.96 (s, 1H), 5.26 (br s, 1H), 5.03 (br s, 2H), 3.77 (s, 2H), 3.34-3.31 (m, 2H), 3.01-2.94 (m, 3H), 2.82-2.75 (m, 1H), 2.08-2.05 (m, 2H), 1.75-1.71 (m, 2H), 1.63-1.53 (m, 1H), 1.42-1.33 (m, 2H), 0.84-0.83 (m, 2H), 0.62-0.58 (m, 2H);
Mass data (APCI, Pos.): m/z 489 (M + H)+.
実施例165:
4−アミノ−5−シアノ−6−(2−ヒドロキシエチルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.59-8.58 (m, 1H), 8.16-8.14 (m, 1H), 7.95-7.92 (m, 1H), 7.80-7.77 (m, 1H), 7.67 (s, 1H), 7.32-7.29 (m, 1H), 6.94 (s, 1H), 5.45-5.42 (m, 1H), 5.11 (s, 2H), 3.88 (t, J = 5.4 Hz, 2H), 3.77 (s, 2H), 3.69-3.67 (s, 2H), 3.34 (t, J = 5.9 Hz, 2H), 2.98-2.95 (m, 2H), 2.10-2.05 (m, 3H), 1.71-1.58 (m, 3H), 1.45-1.35 (m, 1H);
Mass data (APCI, Pos.): m/z 493 (M + H)+.
実施例166:
4−アミノ−5−シアノ−6−(2−メトキシエチルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.96-7.93 (m, 1H), 7.80-7.77 (m, 1H), 7.67 (s, 1H), 7.31-7.29 (m, 1H), 6.94 (s, 1H), 5.36-5.33 (m, 1H), 1.97 (s, 2H), 3.77 (s, 2H), 3.67-3.64 (m, 2H), 3.59-3.57 (m, 2H), 3.39 (s, 3H), 3.31 (t, J = 6.5 Hz, 2H), 3.01-2.94 (m, 3H), 2.08-2.04 (m, 1H), 1.73-1.70 (m, 2H), 1.63-1.53 (m, 1H), 1.41-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 507 (M + H)+.
実施例167:
4−アミノ−5−シアノ−6−(2−(ジメチルアミノ)エチルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.96-7.93 (m, 1H), 7.80-7.76 (m, 1H), 7.67 (s, 1H), 7.31-7.26 (m, 1H), 6.91 (s, 1H), 5.69-5.65 (m, 1H), 5.00 (s, 2H), 3.77 (s, 2H), 3.51-3.49 (m, 2H), 3.31 (t, J = 6.5 Hz, 2H), 2.98-2.95 (m, 2H), 2.55 (t, J = 6.1 Hz, 2H), 2.28 (s, 6H), 2.06-2.04 (m, 2H), 1.74-1.71 (m, 2H), 1.63-1.53 (m, 1H), 1.41-1.31 (m, 2H);
Mass data (APCI, Pos.): m/z 520 (M + H)+.
実施例168:
4−アミノ−5−シアノ−6−((2−ヒドロキシエチル)(メチル)アミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.83-7.77 (m, 2H), 7.68 (s, 1H), 7.32-7.29 (m, 1H), 6.94 (s, 1H), 5.21 (s, 2H), 3.94-3.92 (m, 2H), 3.81-3.77 (m, 3H), 3.40 (s, 3H), 3.34 (t, J = 5.7 Hz, 2H), 2.98-2.96 (m, 2H), 2.10-2.05 (m, 2H), 1.70-1.57 (m, 3H), 1.44-1.41 (m, 2H) 1.26 (t, J = 7.1 Hz, 1H);
Mass data (APCI, Pos.): m/z 507 (M + H)+.
実施例169:
4−アミノ−6−(ビス(2−ヒドロキシエチル)アミノ)−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.56-8.54 (m, 1H), 8.17-8.15 (m, 1H), 7.83-7.78 (m, 2H), 7.67 (s, 1H), 7.35-7.21 (m, 1H), 6.94 (s, 1H), 5.17 (m, 2H), 4.58 (br s, 2H), 4.10-4.08 (m, 4H), 4.01-3.98 (m, 4H), 3.74 (s, 2H), 3.43-3.41 (m, 2H), 2.99-2.96 (m, 2H), 2.13-2.07 (m, 2H), 1.71-1.63 (m, 3H), 1.47-1.38 (m, 2H);
Mass data (APCI, Pos.): m/z 537 (M + H)+.
実施例170:
(S)−4−アミノ−5−シアノ−6−(1−ヒドロキシプロパン−2−イルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.16-8.14 (m, 1H), 7.92-7.90 (m, 1H), 7.81-7.77 (m, 1H), 7.68 (s, 1H), 7.33-7.29 (m, 1H), 6.91 (s, 1H), 5.03-5.01 (m, 3H), 4.31-4.25 (m, 1H), 3.77-3.73 (m, 4H), 3.46-3.40 (m, 1H), 3.29-3.22 (m, 1H), 2.99-2.94 (m, 1H), 2.11-2.02 (m, 3H), 1.72-1.58 (m, 3H), 1.46-1.37 (m, 2H), 1.32 (d, J = 6.7 Hz, 3H), 1.26 (t, J = 7.1 Hz, 1H);
Mass data (APCI, Pos.): m/z 507 (M + H)+.
実施例171:
4−アミノ−5−シアノ−6−(ピペリジン−1−イル)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.94-7.92 (m, 1H), 7.81-7.78 (m, 1H), 7.67 (s, 1H), 7.31-7.28 (m, 1H), 7.00 (s, 1H), 5.10 (s, 2H), 3.78 (s, 2H), 3.60-3.58 (m, 4H), 3.32 (t, J = 6.5 Hz, 2H), 3.01-2.94 (m, 5H), 2.09-2.04 (m, 2H), 1.73-1.57, (m, 8H), 1.42-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 517 (M + H)+.
実施例172:
(R)−4−アミノ−5−シアノ−6−(1−ヒドロキシプロパン−2−イルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.93-7.91 (m, 1H), 7.80-7.77 (m, 1H), 7.68 (s, 1H), 7.32-7.29 (m, 1H), 6.92 (s, 1H), 5.08 (s, 2H), 5.04-5.02 (m, 1H), 4.30-4.25 (m, 1H), 3.77-3.72 (m, 4H), 3.45-3.40 (m, 1H), 3.29-3.23 (m, 1H), 3.00-2.94 (m, 2H), 2.10-2.04 (m, 2H), 1.72-1.59 (m, 3H), 1.45-1.37 (m, 2H), 1.32 (d, J = 6.7 Hz, 3H), 1.26 (t, J = 7.1 Hz, 1H);
Mass data (APCI, Pos.): m/z 507 (M + H)+.
実施例173:
4−アミノ−5−シアノ−6−(3−ヒドロキシアゼチジン−1−イル)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.58-8.56 (m, 1H), 8.21-8.19 (m, 1H), 8.10-8.06 (m, 1H), 7.83-7.80 (m, 1H), 7.68 (s, 1H), 7.35-7.32 (m, 1H), 6.85 (s, 1H), 4.98 (s, 2H), 4.88-4.82 (m, 1H), 4.61-4.57 (m, 2H), 4.25-4.21 (m, 2H), 3.74 (s, 2H), 3.37-3.34 (m, 2H), 2.98-2.95 (m, 2H), 2.08-2.03 (m, 2H), 1.67-1.64 (m, 2H), 1.52-1.43 (m, 2H), 1.26 (t, J = 7.1 Hz, 2H);
Mass data (APCI, Pos.): m/z 505 (M + H)+.
実施例174:
4−アミノ−6−(アゼチジン−1−イル)−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.96-7.94 (m, 1H), 7.80-7.76 (m, 1H), 7.67 (s, 1H), 7.31-7.28 (m, 1H), 6.85 (s, 1H), 4.94 (s, 2H), 4.34-4.30 (m, 4H), 3.77 (s, 2H), 3.30 (t, J = 6.5 Hz, 2H), 2.97-2.94 (m, 2H), 2.42-2.36 (m, 2H), 2.09-2.04 (m, 2H), 1.71-1.69 (m, 2H), 1.61-1.52 (m, 1H), 1.39-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 489 (M + H)+.
実施例175:
(R)−4−アミノ−5−シアノ−6−(2−ヒドロキシプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.90-7.88 (m, 1H), 7.80-7.76 (m, 1H), 7.67 (s, 1H), 7.32-7.29 (m, 1H), 6.94 (s, 1H), 5.45-5.43 (m, 1H), 5.13 (s, 2H), 4.15-4.06 (m, 1H), 3.77 (s, 2H), 3.65-3.57 (m, 2H), 3.44-3.30 (m, 3H), 2.98-2.95 (m, 2H), 2.11-2.04 (m, 2H), 1.72-1.69 (m, 2H), 1.65-1.56 (m, 1H), 1.43-1.37 (m, 2H), 1.26 (d, J = 6.2 Hz, 3H);
Mass data (APCI, Pos.): m/z 507 (M + H)+.
実施例176:
(S)−4−アミノ−5−シアノ−6−(2−ヒドロキシプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.90-7.88 (m, 1H), 7.80-7.77 (m, 1H), 7.67 (s, 1H), 7.32-7.29 (m, 1H), 6.95 (s, 1H), 5.45-5.43 (m, 1H), 5.14 (s, 2H), 4.15-4.06 (m, 1H), 3.77 (s, 2H), 3.65-3.57 (m, 2H), 3.44-3.30 (m, 3H), 2.98-2.95 (m, 2H), 2.11-2.04 (m, 2H), 1.72-1.69 (m, 2H), 1.65-1.56 (m, 1H), 1.43-1.37 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H);
Mass data (APCI, Pos.): m/z 507 (M + H)+.
実施例177:
4−アミノ−5−シアノ−6−(3−ヒドロキシプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.16-8.14 (m, 1H), 8.04-8.06 (m, 1H), 7.80-7.77 (m, 1H), 7.68 (s, 1H), 7.32-7.29 (m, 1H), 6.89 (s, 1H), 5.43-5.40 (m, 1H), 5.00 (s, 2H), 3.79-3.76 (m, 4H), 3.68-3.65 (m, 2H), 3.35-3.33 (m, 2H), 2.99-2.97 (m, 2H), 2.75 (br s, 1H), 2.08-2.05 (m, 2H), 1.91-1.86 (m, 2H), 1.71-1.62 (m, 3H), 1.49-1.40 (m, 2H);
Mass data (APCI, Pos.): m/z 507 (M + H)+.
実施例178:
(S)−4−アミノ−5−シアノ−6−(1−ヒドロキシブタン−2−イルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.59-8.57 (m, 1H), 8.15-8.13 (m, 1H), 7.90-7.88 (m, 1H), 7.81-7.77 (m, 1H), 7.68 (s, 1H), 7.32-7.29 (m, 1H), 6.90 (s, 1H), 5.01 (s, 2H), 4.15-4.05 (m, 1H), 3.77-3.76 (m, 3H), 3.46-3.39 (m, 1H), 3.33-3.21 (m, 1H), 2.99-2.93 (m, 2H), 2.10-2.05 (m, 2H), 1.83-1.58 (m, 6H), 1.45-1.36 (m, 2H), 1.28-1.23 (m, 2H), 1.01 (t, J = 7.5 Hz, 2H);
Mass data (APCI, Pos.): m/z 521 (M + H)+.
実施例179:
(R)−4−アミノ−5−シアノ−6−(1−ヒドロキシブタン−2−イルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.59-8.57 (m, 1H), 8.16-8.14 (m, 1H), 7.90-7.88 (m, 1H), 7.81-7.77 (m, 1H), 7.68 (s, 1H), 7.33-7.29 (m, 1H), 6.90 (s, 1H), 5.00 (s, 2H), 4.15-4.05 (m, 1H), 3.77-3.76 (m, 3H), 3.46-3.39 (m, 1H), 3.33-3.22 (m, 1H), 2.99-2.93 (m, 2H), 2.10-2.05 (m, 2H), 1.82-1.58 (m, 6H), 1.45-1.36 (m, 2H), 1.28-1.24 (m, 2H), 1.01 (t, J = 7.5 Hz, 2H);
Mass data (APCI, Pos.): m/z 521 (M + H)+.
実施例180:
4−アミノ−5−シアノ−6−(2−モルホリノエチルアミン)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.98-7.96 (m, 1H), 7.81-7.77 (m, 1H), 7.67 (s, 1H), 7.33-7.29 (m, 1H), 6.90 (s, 1H), 5.80-5.78 (m, 1H), 4.95 (s, 2H), 3.77-3.73 (m, 7H), 3.53-3.50 (m, 2H), 3.32 (t, J = 6.5 Hz, 2H), 2.98-2.95 (m, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.52-2.49 (m, 4H), 2.09-2.04 (m, 2H), 1.74-1.70 (m, 2H), 1.39-1.33 (m, 2H);
Mass data (APCI, Pos.): m/z 562 (M + H)+.
実施例181:
(R)−4−アミノ−5−シアノ−6−(2,3−ジヒドロキシプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.92-7.90 (m, 1H), 7.81-7.76 (m, 1H), 7.69 (s, 1H), 7.33-7.30 (m, 1H), 6.90 (s, 1H), 5.46-5.44 (m, 1H), 4.99 (s, 2H), 4.02-3.97 (m, 1H), 3.78-3.73 (m, 3H), 3.67-3.62 (m, 2H), 3.39-3.34 (m, 3H), 3.02-2.98 (m, 2H), 2.12-2.04 (m, 2H), 1.68-1.65 (m, 3H), 1.58-1.53 (m, 3H);
Mass data (APCI, Pos.): m/z 523 (M + H)+.
実施例182:
(S)−4−アミノ−5−シアノ−6−(2,3−ジヒドロキシプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.16-8.14 (m, 1H), 7.92-7.90 (m, 1H), 7.81-7.77 (m, 1H), 7.69 (s, 1H), 7.33-7.30 (m, 1H), 6.90 (s, 1H), 5.46-5.44 (m, 1H), 4.99 (s, 2H), 4.02-3.98 (m, 1H), 3.78-3.73 (m, 3H), 3.67-3.62 (m, 2H), 3.40-3.35 (m, 3H), 3.02-2.99 (m, 2H), 2.12-2.04 (m, 2H), 1.68-1.66 (m, 3H), 1.57-1.53 (m, 3H);
Mass data (APCI, Pos.): m/z 523 (M + H)+.
実施例183:
4−アミノ−5−シアノ−6−(1−メチルピペリジン−4−イルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.94-7.92 (m, 1H), 7.80-7.76 (m, 1H), 7.68 (s, 1H), 7.32-7.29 (m, 1H), 6.88 (s, 1H), 5.46-5.44 (m, 1H), 4.95 (s, 2H), 4.89-4.86 (m, 1H), 3.90 (br s, 1H), 3.78 (s, 2H), 3.32 (t, J = 6.4 Hz, 2H), 2.99-2.96 (m, 2H), 2.82-2.80 (m, 2H), 2.28 (s, 3H), 2.17-2.02 (m, 6H), 1.72-1.70 (m, 2H), 1.64-1.56 (m, 2H), 1.41-1.36 (m, 2H);
Mass data (APCI, Pos.): m/z 546 (M + H)+.
実施例184:
4−アミノ−5−シアノ−6−(4−ヒドロキシピペリジン−1−イル)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.17-8.15 (m, 1H), 7.95-7.93 (m, 1H), 7.81-7.78 (m, 1H), 7.67 (s, 1H), 7.33-7.29 (m, 1H), 7.04 (s, 1H), 5.16 (s, 2H), 4.07-4.02 (m, 3H), 3.76 (s, 2H), 3.42-3.33 (m, 4H), 2.99-2.96 (m, 2H), 2.28 (s, 1H), 2.10-2.02 (m, 4H), 1.77-1.58 (m, 5H), 1.47-1.35 (m, 2H);
Mass data (APCI, Pos.): m/z 533 (M + H)+.
実施例185:
4−アミノ−5−シアノ−6−(4−(ヒドロキシメチル)ピペリジン−1−イル)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.16-8.14 (m, 1H), 7.95-7.93 (m, 1H), 7.81-7.77 (m, 1H), 7.68 (s, 1H), 7.33-7.29 (m, 1H), 7.01 (s, 1H), 5.09 (s, 2H), 4.32-4.29 (m, 2H), 3.77 (s, 2H), 3.57 (t, J = 6.2 Hz, 4H), 3.34 (t, J = 6.2 Hz, 3H), 3.06-2.94 (m, 3H), 2.10-2.03 (m, 2H), 1.89-1.78 (m, 2H), 1.72-1.69 (m, 2H), 1.65-1.55 (m, 1H), 1.47-1.35 (m, 4H);
Mass data (APCI, Pos.): m/z 547 (M + H)+.
実施例186:
4−アミノ−5−シアノ−6−(3−(ジメチルアミノ)プロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 8.05-8.02 (m, 1H), 7.80-7.76 (m, 1H), 7.67 (s, 1H), 7.58 (s, 1H), 7.32-7.28 (m, 1H), 6.84 (s, 1H), 4.88 (s, 2H), 3.77 (s, 2H), 3.56-3.53 (m, 2H), 3.31 (t, J = 6.5 Hz, 3H), 2.97-2.95 (m, 2H), 2.50-2.47 (m, 2H), 2.29 (s, 6H), 2.09-2.04 (m, 2H), 1.79-1.71 (m, 3H), 1.63-1.54 (m, 1H), 1.40-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 534 (M + H)+.
実施例187:
4−アミノ−6−(3−アミノプロピルアミノ)−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.61-8.59 (m, 1H), 8.15-8.13 (m, 1H), 8.09-8.04 (m, 1H), 7.81-7.77 (m, 1H), 7.67 (s, 1H), 7.32-7.28 (m, 1H), 6.86-6.84 (m, 1H), 4.95-4.87 (m, 2H), 3.77 (s, 2H), 3.65-3.56 (m, 4H), 3.34-3.29 (m, 2H), 2.97-2.91 (m, 2H), 2.09-2.02 (m, 4H), 1.83-1.74 (m, 4H), 1.39-1.32 (m, 4H);
Mass data (APCI, Pos.): m/z 506 (M + H)+.
実施例188:
4−アミノ−5−シアノ−6−(4−(ジメチルアミノ)ピペリジン−1−イル)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.61-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.91-7.89 (m, 1H), 7.81-7.77 (m, 1H), 7.67 (s, 1H), 7.31-7.29 (m, 1H), 7.02 (s, 1H), 5.09 (s, 2H), 4.32-4.29 (m, 2H), 3.77 (s, 2H), 3.32 (t, J = 6.5 Hz, 2H), 3.03-2.96 (m, 4H), 2.45-2.36 (m, 1H), 2.23 (s, 6H), 2.10-2.05 (m, 2H), 1.96-1.93 (m, 2H), 1.73-1.58 (m, 5H), 1.38-1.35 (m, 2H);
Mass data (APCI, Pos.): m/z 560 (M + H)+.
実施例189:
4−アミノ−5−シアノ−6−(3−モルホリノプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.61-8.59 (m, 1H), 8.15-8.13 (m, 1H), 8.00-7.98 (m, 1H), 7.81-7.77 (m, 1H), 7.67 (s, 1H), 7.32-7.29 (m, 1H), 6.87 (s, 1H), 6.68-6.66 (m, 1H), 4.93 (s, 2H), 3.84-3.81 (m, 4H), 3.77 (s, 2H), 3.57-3.54 (m, 2H), 3.32 (t, J = 6.5 Hz, 2H), 2.98-2.95 (m, 2H), 2.54-2.49 (m, 6H), 2.09-2.04 (m, 2H), 1.86-1.79 (m, 2H), 1.74-1.70 (m, 2H), 1.64-1.56 (m, 1H), 1.41-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 576 (M + H)+.
実施例190:
6−(3−(1H−イミダゾール−1−イル)プロピルアミノ)−4−アミノ−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.79-7.77 (m, 1H), 7.75-7.71 (m, 1H) 7.68 (s, 1H), 7.08 (s, 1H), 6.92 (s, 2H), 5.01-4.97 (m, 1H), 4.95 (s, 2H), 4.07 (t, J = 6.7 Hz, 2H), 3.77 (s, 2H), 3.52-3.45 (m, 2H), 3.37-3.33 (m, 2H), 2.98-2.95 (m, 2H), 2.10-2.04 (m, 2H), 1.72-1.67 (m, 2H), 1.57 (s, 4H), 1.42-1.33 (m, 2H);
Mass data (APCI, Pos.): m/z 557 (M + H)+.
実施例191:
6−(2−(1H−イミダゾール−1−イル)エチルアミノ)−4−アミノ−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 7.80-7.77 (m, 1H), 7.75-7.71 (m, 1H) 7.67 (s, 1H), 7.49 (s, 1H), 7.32-7.28 (m, 1H), 7.07 (s, 1H), 6.96 (s, 1H), 6.93 (s, 1H), 5.30-5.27 (m, 1H), 5.17 (s, 2H), 4.21 (t, J = 5.9 Hz, 2H), 3.86-3.83 (m, 2H), 3.77 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.99-2.96 (m, 2H), 2.10-2.04 (m, 2H), 1.73-1.69 (m, 2H), 1.64-1.56 (m, 1H), 1.42-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 543 (M + H)+.
実施例192:
4−アミノ−6−(3−アミノ−3−オキソプロピルアミノ)−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.58 (m, 1H), 8.15-8.13 (m, 1H), 8.08-8.06 (m, 1H), 7.81-7.76 (m, 1H), 7.67 (s, 1H), 7.32-7.28 (m, 1H), 6.90 (s, 1H), 5.64-5.59 (m, 2H), 5.40 (s, 1H), 4.95 (s, 2H), 3.85-3.80 (m, 2H), 3.76 (s, 2H), 3.34 (t, J = 6.2 Hz, 2H), 2.98-2.95 (m, 2H), 2.56 (t, J = 6.1 Hz, 2H), 2.10-2.04 (m, 2H), 1.74-1.69 (m, 2H), 1.65-1.58 (m, 1H), 1.44-1.35 (m, 2H);
Mass data (APCI, Pos.): m/z 520 (M + H)+.
実施例193:
6−(2−(1H−イミダゾール−4−イル)エチルアミノ)−4−アミノ−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.16-8.14 (m, 2H), 7.82-7.78 (m, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.33-7.30 (m, 1H), 6.87 (s, 1H), 6.84 (s, 1H), 5.59-5.57 (m, 1H), 5.03 (s, 2H), 3.78-3.74 (m, 5H), 3.32 (t, J = 6.4 Hz, 2H), 2.94-2.92 (m, 4H), 2.08-2.03 (m, 2H), 1.72-1.70 (m, 2H), 1.64-1.56 (m, 1H), 1.39-1.34 (m, 2H);
Mass data (APCI, Pos.): m/z 543 (M + H)+.
実施例194:
4−アミノ−6−(3−アミノ−2−ヒドロキシプロピルアミノ)−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.94-7.91 (m, 1H), 7.80-7.77 (m, 1H), 7.67 (s, 1H), 7.32-7.29 (m, 1H), 6.90 (s, 1H), 5.62 (s, 1H), 5.02 (s, 2H), 3.83-3.77 (m, 3H), 3.68-3.63 (m, 2H), 3.55-3.48 (m, 2H), 3.34-3.30 (m, 2H), 2.99-2.91 (m, 3H), 2.74-2.69 (m, 1H), 2.10-2.02 (m, 2H), 1.73-1.68 (m, 2H), 1.63-1.56 (m, 2H), 1.40-1.35 (m, 2H);
Mass data (APCI, Pos.): m/z 522 (M + H)+.
実施例195:
4−アミノ−5−シアノ−6−(1,3−ジヒドロキシプロパン−2−イルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CD3OD): d 8.57 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.94-7.87 (m, 1H), 7.74 (s, 1H), 7.45-7.39 (m, 1H), 6.78 (s, 1H), 4.35-4.28 (m, 1H), 3.82 (s, 2H), 3.78-3.66 (m, 4H), 3.37-3.25 (m, 2H), 3.03-2.94 (m, 2H), 2.15-2.06 (m, 2H), 1.80-1.71 (m, 2H), 1.69-1.58 (m, 1H), 1.43-1.28 (m, 2H);
Mass data (APCI, Pos.): m/z 523 (M + H)+.
実施例196:
4−アミノ−6−(tert−ブチルアミノ)−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.88-7.85 (m, 1H), 7.81-7.76 (m, 1H), 7.67 (s, 1H), 7.32-7.29 (m, 1H), 6.85 (s, 1H), 4.92 (s, 1H), 4.84 (s, 2H), 3.77 (s, 2H), 3.33 (t, J = 6.4 Hz, 2H), 2.98-2.95 (m, 2H), 2.09-2.03 (m, 2H), 1.75-1.71 (m, 1H), 1.49 (s, 9H), 1.41-1.35 (m, 2H), 1.24 (s, 2H);
Mass data (APCI, Pos.): m/z 505 (M + H)+.
実施例197:
4−アミノ−5−シアノ−6−(イソプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.99-7.97 (m, 1H), 7.81-7.78 (m, 1H), 7.70 (s, 1H), 7.32-7.29 (m, 1H), 6.87 (s, 1H), 4.92 (s, 1H), 4.81-4.79 (m, 1H), 3.81 (s, 2H), 3.33 (t, J = 6.5 Hz, 2H), 3.01-2.95 (m, 3H), 2.09-2.03 (m, 2H), 1.75-1.72 (m, 2H), 1.44-1.38 (m, 4H), 1.27 (d, J = 6.5 Hz, 6H);
Mass data (APCI, Pos.): m/z 491 (M + H)+.
実施例198:
4−アミノ−5−シアノ−6−(シクロプロピルメチルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.61-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.97-7.95 (m, 1H), 7.81-7.77 (m, 1H), 7.67 (s, 1H), 7.33-7.29 (m, 1H), 6.88 (s, 1H), 5.13-5.11 (m, 1H), 4.92 (s, 2H), 3.77 (s, 2H), 3.33-3.29 (m, 4H), 2.97-2.94 (m, 2H), 2.09-2.05 (m, 2H), 1.74-1.70 (m, 2H), 1.42-1.33 (m, 2H), 1.14-1.05 (m, 1H), 0.92 (d, J = 6.7 Hz, 1H), 0.60-0.54 (m, 2H), 0.29-0.26 (m, 2H);
Mass data (APCI, Pos.): m/z 503 (M + H)+.
実施例199:
4−アミノ−5−シアノ−6−(エチルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.61-8.59 (m, 1H), 8.15-8.13 (m, 1H), 8.01-7.99 (m, 1H), 7.81-7.77 (m, 1H), 7.68 (s, 1H), 7.33-7.29 (m, 1H), 6.90 (s, 1H), 5.50 (s, 1H), 5.02 (s, 2H), 4.97-4.95 (m, 1H), 3.78 (s, 2H), 3.52-3.47 (m, 2H), 3.33-3.26 (m, 2H), 3.01-2.94 (m, 2H), 2.11-2.05 (m, 2H), 1.97 (s, 1H), 1.74-1.71 (m, 2H), 1.63-1.57 (m, 1H), 1.41-1.33 (m, 2H), 1.27 (t, J = 7.2 Hz, 1H);
Mass data (APCI, Pos.): m/z 477 (M + H)+.
実施例200:
4−アミノ−5−シアノ−6−プロポキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.80-7.76 (m, 2H), 7.67 (s, 1H), 7.31-7.26 (m, 1H), 7.20 (s, 1H), 5.13 (s, 2H), 4.32 (t, J = 6.5 Hz, 2H), 3.78 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.98-2.95 (m, 2H), 2.10-2.05 (m, 2H), 1.88-1.80 (m, 2H), 1.74-1.70 (m, 2H), 1.63-1.58 (m, 1H), 1.42-1.34 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H);
Mass data (APCI, Pos.): m/z 492 (M + H)+.
実施例201:
4−アミノ−5−シアノ−6−(2−ヒドロキシエトキシ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CD3OD): d 8.57-8.56 (m, 1H), 8.13-8.11 (m, 1H), 7.93-7.88 (m, 1H), 7.75 (s, 1H), 7.44-7.41 (m, 1H), 7.09 (s, 1H), 4.53-4.51 (m, 3H), 3.90-3.87 (m, 2H), 3.83 (s, 2H), 3.31-3.29 (m, 4H), 3.01-2.98 (m, 2H), 2.15-2.10 (m, 2H), 1.77-1.73 (m, 2H), 1.70-1.62 (m, 1H), 1.41-1.33 (m, 2H);
Mass data (APCI, Pos.): m/z 494 (M + H)+.
実施例202:
4−アミノ−5−シアノ−6−(3−ヒドロキシプロポキシ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CD3OD): d 8.57-8.56 (m, 1H), 8.13-8.11 (m, 1H), 7.93-7.88 (m, 1H), 7.75 (s, 1H), 7.44-7.41 (m, 1H), 7.08 (s, 1H), 4.85-4.81 (m, 3H), 4.55 (t, J = 6.3 Hz, 2H), 3.83 (s, 2H), 3.73 (t, J = 6.2 Hz, 2H), 3.33-2.26 (m, 4H), 3.01-2.98 (m, 2H), 2.14-2.09 (m, 2H), 2.01-1.96 (m, 2H), 1.76-1.73 (m, 2H), 1.69-1.62 (m, 1H), 1.42-1.32 (m, 2H);
Mass data (APCI, Pos.): m/z 508 (M + H)+.
実施例203:
4−アミノ−5−シアノ−6−イソプロポキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60-8.59 (m, 1H), 8.15-8.13 (m, 1H), 7.80-7.77 (m, 1H), 7.67 (s, 1H), 7.33-7.29 (m, 1H), 7.17 (s, 1H), 5.31-5.26 (m, 1H), 5.12 (s, 2H), 3.78 (s, 2H), 3.68-3.63 (m, 2H), 3.33 (t, J = 6.5 Hz, 2H), 2.99-2.96 (m, 2H), 2.11-2.05 (m, 2H), 1.73-1.70 (m, 2H), 1.65-1.56 (m, 2H), 1.40 (d, J = 6.2 Hz, 6H);
Mass data (APCI, Pos.): m/z 592 (M + H)+.
実施例204:
4−アミノ−5−シアノ−6−(1−シクロプロピルエトキシ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
濃縮した。
1H NMR (CDCl3): d 8.60 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.83-7.76 (m, 1H), 7.73 (t, J = 6.2 Hz, 1H), 7.68 (s, 1H), 7.34-7.29 (m, 1H), 7.24 (s, 1H), 5.35 (s, 2H), 4.75-4.66 (m, 1H), 3.78 (s, 2H), 3.32 (t, J = 6.5 Hz, 2H), 3.02-2.92 (m, 2H), 2.12-2.02 (m, 2H), 1.76-1.65 (m, 2H), 1.64-1.54 (m, 1H), 1.43 (d, J = 6.3 Hz, 3H), 1.40-1.31 (m, 2H), 1.22-1.14 (m, 1H), 0.60-0.51 (m, 2H), 0.47-0.41 (m, 1H), 0.36-0.28 (m, 1H);
Mass data (APCI, Pos.): m/z 518 (M + H)+.
実施例205:
4−アミノ−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−(3,3,3−トリフルオロプロポキシ)ピコリンアミド
1H NMR (CDCl3): d 8.60 (d, J = 4.8 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.82-7.75 (m, 1H), 7.74-7.66 (m, 2H), 7.33-7.28 (m, 1H), 7.24 (s, 1H), 5.18 (s, 2H), 4.63 (t, J = 6.8 Hz, 2H), 3.78 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 3.02-2.92 (m, 2H), 2.74-2.63 (m, 2H), 2.13-2.02 (m, 2H), 1.77-1.67 (m, 2H), 1.65-1.58 (m, 1H), 1.44-1.31 (m, 2H);
Mass data (APCI, Pos.): m/z 546 (M + H)+.
実施例206:
4−アミノ−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−(2,2,2−トリフルオロエトキシ)ピコリンアミド
1H NMR (CDCl3): d 8.60 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.82-7.76 (m, 1H), 7.68 (s, 1H), 7.62 (t, J = 6.3 Hz, 1H), 7.37 (s, 1H), 7.33-7.28 (m, 1H), 5.45 (s, 2H), 4.80 (q, J = 8.2 Hz, 2H), 3.78 (s, 2H), 3.35 (t, J = 6.5 Hz, 2H), 3.02-2.92 (m, 2H), 2.13-2.03 (m, 2H), 1.76-1.66 (m, 2H), 1.61-1.54 (m, 1H), 1.44-1.30 (m, 2H);
Mass data (APCI, Pos.): m/z 532 (M + H)+.
実施例207:
(R)−4−アミノ−5−シアノ−6−(3−ヒドロキシブトキシ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.07-7.92 (m, 1H), 7.83-7.76 (m, 1H), 7.68 (s, 1H), 7.35-7.29 (m, 1H), 7.24-7.19 (m, 1H), 5.38-5.28 (m, 2H), 4.64-4.50 (m, 2H), 4.12-4.03 (m 1H), 3.64 (s, 2H), 3.34 (t, J = 6.1 Hz, 2H), 3.03-2.93 (m, 2H), 2.13-1.81 (m, 4H), 1.74-1.57 (m, 3H), 1.49-1.37 (m, 2H), 1.28 (d, J = 6.2 Hz, 3H);
Mass data (APCI, Pos.): m/z 522 (M + H)+.
実施例208:
(S)−4−アミノ−5−シアノ−6−(3−ヒドロキシブトキシ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.60 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.07-7.92 (m, 1H), 7.83-7.76 (m, 1H), 7.68 (s, 1H), 7.35-7.29 (m, 1H), 7.24-7.19 (m, 1H), 5.38-5.28 (m, 2H), 4.64-4.50 (m, 2H), 4.12-4.03 (m 1H), 3.64 (s, 2H), 3.34 (t, J = 6.1 Hz, 2H), 3.03-2.93 (m, 2H), 2.13-1.81 (m, 4H), 1.74-1.57 (m, 3H), 1.49-1.37 (m, 2H), 1.28 (d, J = 6.2 Hz, 3H);
Mass data (APCI, Pos.): m/z 522 (M + H)+.
実施例209:
(R)−4−アミノ−6−(1−(tert−ブチルジメチルシリルオキシ)プロパン−2−イルオキシ)−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
Mass data (APCI, Pos.): m/z 622 (M + H)+.
実施例210:
(S)−4−アミノ−6−(1−(tert−ブチルジメチルシリルオキシ)プロパン−2−イルオキシ)−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
Mass data (APCI, Pos.): m/z 622 (M + H)+.
実施例211:
(R)−4−アミノ−5−シアノ−6−(1−ヒドロキシプロパン−2−イルオキシ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): d 8.59 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.82-7.73 (m, 2H), 7.67 (s, 1H), 7.34-7.25 (m, 2H), 5.41-5.32 (m, 2H), 4.36-4.21 (m, 2H), 3.89-3.78 (m, 3H), 3.37-3.32 (m, 2H), 3.01-2.92 (m, 2H), 2.13-2.02 (m, 2H), 1.76-1.66(m, 2H), 1.65-1.55 (m, 1H), 1.45-1.28 (m, 5H);
Mass data (APCI, Pos.): m/z 508 (M + H)+.
実施例212:
(S)−4−アミノ−5−シアノ−6−(1−ヒドロキシプロパン−2−イルオキシ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド.
1H NMR (CDCl3): d 8.60 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.82-7.76 (m, 1H), 7.68 (s, 1H), 7.62 (t, J = 6.3 Hz, 1H), 7.37 (s, 1H), 7.33-7.28 (m, 1H), 5.45 (s, 2H), 4.80 (q, J = 8.2 Hz, 2H), 3.78 (s, 2H), 3.35 (t, J = 6.5 Hz, 2H), 3.02-2.92 (m, 2H), 2.13-2.03 (m, 2H), 1.76-1.66 (m, 2H), 1.61-1.54 (m, 1H), 1.44-1.30 (m, 2H);
Mass data (APCI, Pos.): m/z 532 (M + H)+.
実施例213:
tert−ブチル (1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチルカルバメート
1H NMR (CDCl3): d 8.60 (d, J = 4.7 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.78 (dt, J = 7.8, 1.6 Hz, 1H), 7.67 (s, 1H), 7.31-7.28 (m, 1H), 4.58 (bs, 1H), 3.77 (s, 2H), 3.03-3.00 (m, 2H), 2.96-2.93 (m, 2H), 2.05 (dt, J = 11.7, 2.3 Hz, 2H), 1.67 (d, J = 12.5 Hz, 2H), 1.43 (s, 9H), 1.29 (dt, J = 11.7, 3.1 Hz, 2H);
Mass data (ESI, Pos.): m/z 411 (M + Na)+.
実施例214:
(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メタンアミン 三塩酸塩
1H NMR (DMSO-d6): d 11.35 (bs, 1H), 8.66 (d, J = 4.7 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.13 (s, 1H), 8.08 (bs, 3H), 8.00 (dt, J = 7.8, 1.6 Hz, 1H), 7.56-7.53 (m, 1H), 4.61 (d, J = 4.7 Hz, 2H), 3.45-3.42 (m, 2H), 3.17 (bs, 1H), 2.98-2.90 (m, 2H), 2.73-2.68 (m, 2H), 1.97-1.93 (m, 2H), 1.86 (bs, 1H), 1.62-1.53 (m, 2H);
Mass data (ESI, Pos.): m/z 289 (M +H)+.
実施例215:
4−アミノ−6−クロロ−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): d 8.61 (d, J = 4.8 Hz, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.97-7.91 (m, 1H), 7.78 (s, 1H), 7.74 (s, 2H), 7.49-7.44 (m 1H), 7.35 (s, 1H), 3.73 (s, 2H), 3.18-3.12 (m, 2H), 2.89-2.81 (m, 2H), 2.00-1.90 (m 2H), 1.64-1.50 (m, 3H), 1.23-1.11 (m, 2H);
Mass data (APCI, Pos.): m/z 468 (M + H)+.
実施例216:
(R)−4−(tert−ブチルジメチルシリルオキシ)ブタン−2−オール
1H NMR (CDCl3): d 4.06-3.98 (m, 1H), 3.93-3.87 (m, 1H), 3.84-3.77 (m, 1H), 3.36 (d, J = 2.4 Hz, 1H), 1.71-1.59 (m, 2H), 1.19 (d, J = 6.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H).
実施例217:
(S)−4−(tert−ブチルジメチルシリルオキシ)ブタン−2−オール
1H NMR (CDCl3): d 4.06-3.98 (m, 1H), 3.92-3.87 (m, 1H), 3.84-3.78 (m, 1H), 3.36 (d, J = 2.4 Hz, 1H), 1.72-1.59 (m, 2H), 1.19 (d, J = 6.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H).
実施例218:
(R)−1−(tert−ブチルジメチルシリルオキシ)プロパン−2−オール
1H NMR (CDCl3): d 3.86-3.78 (m, 1H), 3.59 (dd, J = 3.4, 9.9 Hz, 1H), 3.35 (dd, J = 7.8 9.9 Hz, 1H), 2.45 (d, J = 3.2 Hz), 1.12 (d, J = 6.3 Hz), 0.91 (s, 9H), 0.08 (s, 6H).
実施例219:
(S)−1−(tert−ブチルジメチルシリルオキシ)プロパン−2−オール
1H NMR (CDCl3): d 3.86-3.78 (m, 1H), 3.60 (dd, J = 3.4, 9.9 Hz, 1H), 3.35 (dd, J = 7.8 9.9 Hz, 1H), 2.45 (d, J = 3.2 Hz), 1.12 (d, J = 6.3 Hz), 0.91 (s, 9H), 0.08 (s, 6H).
実施例220:
(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メタノール
1H NMR (CDCl3): d 8.60 (d, J = 4.1 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.82-7.74 (m, 1H), 7.69 (s, 1H), 7.34-7.28 (m, 1H), 3.79 (s, 2H), 3.55-3.45 (m, 2H), 3.03-2.92 (m, 2H), 2.12-2.00 (m, 2H), 1.78-1.68 (m, 2H), 1.55-1.44 (m, 1H), 1.39-1.22 (m, 3H);
Mass data (APCI, Pos.): m/z 29 (M + H)+.
実施例221:
メチル 5−(tert−ブトキシカルボニルアミノ)−4−シアノ−3−メチルチオフェン−2−カルボキシレート
1H NMR (CDCl3): d 7.70 (s, 1H), 3.84 (s, 3H), 2.59 (s, 3H), 1.49 (s, 9H);
Mass data (APCI, Neg.): m/z 295 (M - H)-.
実施例222:
5−(tert−ブトキシカルボニルアミノ)−4−シアノ−3−メチルチオフェン−2−カルボン酸
1H NMR (DMSO-d6): d 13.13 (s, 1H), 11.64 (s, 1H), 2.46 (s, 3H), 1.50 (s, 9H);
Mass data (APCI, Neg.): m/z 281 (M - H)-.
実施例223:
(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル 5−(tert−ブトキシカルボニルアミノ)−4−シアノ−3−メチルチオフェン−2−カルボキシレート
1H NMR (CDCl3): d 8.60 (d, J = 4.6 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.34-7.29 (m 1H), 4.10 (d, J = 6.1 Hz, 2H), 3.79 (s, 2H), 3.04-2.91 (m, 2H), 2.58 (s, 3H), 2.14-2.02 (m, 2H), 1.82-1.66 (m, 3H), 1.56 (s, 9H), 1.45-1.30 (m, 2H);
Mass data (APCI, Pos.): m/z 554 (M + H)+.
実施例224:
(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル 5−アミノ−4−シアノ−3−メチルチオフェン−2−カルボキシレート 三塩酸塩
1H NMR (DMSO-d6): d 10.71 (s, 1H), 8.70-8.63 (m, 1H), 8.18-7.96 (m, 4H), 7.58-7.51 (m, 1H), 5.24 (s, 3H), 4.73-4.63 (m, 2H), 4.20-4.05 (m, 2H), 3.54-3.41 (m, 2H), 3.05-2.90 (m, 2H), 2.38 (s, 3H), 2.01-1.78 (m, 3H), 1.67-1.51 (m, 2H);
Mass data (APCI, Pos.): m/z 454 (M + H (free base))+.
実施例225:
tert−ブチル 4−((4−アミノ−5−シアノ−6−エトキシピコリンアミド)メチル)ピペリジン−1−カルボキシレート
1H NMR (CDCl3): d ppm 7.85-7.78 (m, 1H), 7.20 (s, 1H), 5.18-5.09 (m, 2H), 4.44 (q, J = 7.1 Hz, 2H), 4.22-4.03 (m, 2H), 3.41-3.28 (m, 2H), 2.8-2.6 (m, 2H), 1.82-1.74 (m, 1H), 1.73-1.65 (m, 2H), 1.45 (s, 9H), 1.29-1.12 (m, 3H);
Mass data (ESI, Pos.): m/z 404 (M + H)+.
実施例226:
4−アミノ−5−シアノ−6−エトキシ−N−(ピペリジン−4−イルメチル)ピコリンアミド 二塩酸塩
1H NMR (DMSO-d6): d 8.79-8.68 (m, 1H), 8.63-8.55 (m, 1H), 8.49-8.36 (m, 1H), 7.39-7.26 (m, 2H), 7.05 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 3.28-3.14 (m, 4H), 2.88-2.75 (m, 2H), 1.89-1.70 (m, 3H), 1.42-1.27 (m, 5H);
Mass data (APCI, Pos.): m/z 304 (M + H (free base))+.
実施例227:
5−アミノ−4−シアノ−3−メチルチオフェン−2−カルボン酸
1H NMR (DMSO-d6): d 12.55 (bs, 1H), 8.45 (s, 2H), 2.35 (s, 3H);
Mass data (ESI, Neg.): m/z 181 (M - H)-.
実施例228:
5−アミノ−4−シアノ−3−メチル−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)チオフェン−2−カルボキサアミド
1 H NMR (CDCl3): d 7.72-7.78 (m, 2H), 7.48-7.42 (m, 3H), 6.48 (s, 1H), 5.63 (br t, 1H), 5.10 (s, 2H), 3.74 (s, 2H), 3.29 (t, 2H), 3.29 (br d, 2H), 2.45 (s, 3H), 2.21-2.08 (m, 2H), 1.74 (br d, 2H), 1.58 (m, 1H), 1.42-1.31 (m, 2H);
Mass Data (ESI, Pos.): m/z 436 (M + H)+.
実施例229:
エチル 2−クロロ−6−エトキシイソニコチネート
1H NMR (CDCl3): d 7.41 (s, 1H), 7.21 (s, 1H), 4.38 (q, J = 7.0, 4H), 1.40 (t, J = 7.0, 3H), 1.39 (t, J = 7.0 Hz, 3H);
Mass data (ESI, Pos.): m/z 230 (M +H; Cl)+.
実施例230:
エチル 2−(ジフェニルメチレンアミノ)−6−エトキシイソニコチネート
1H NMR (CDCl3): d 7.82-7.78 (m, 2H), 7.52-7.47 (m, 1H), 7.43-7.39 (m, 2H), 7.30-7.24 (m, 3H), 7.18-7.16 (m, 2H), 6.86 (s, 1H), 6.79 (s, 1H), 4.30 (q, J = 7.0 Hz, 2H), 4.14 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H);
Mass data (ESI, Pos.): m/z 375 (M +H)+.
実施例231:
2−アミノ−6−エトキシ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)イソニコチンアミド
Mass data (ESI, Pos.): m/z 458 (M +Na)+.
実施例232:
ジメチル 4−アミノ−3−シアノピリジン−2,6−ジカルボキシレート
1H NMR (CDCl3): d 7.64 (s, 1H), 5.41 (s, 2H), 4.05 (s, 3H), 4.01 (s, 3H);
Mass data (APCI, Pos.): m/z 236 (M + H)+.
実施例233:
メチル 4−アミノ−3−シアノ−6−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチルカルバモイル)ピコリネート
1H NMR (CDCl3): d 8.60 (d, J = 4.7 Hz, 1H), 8.15-8.10 (m, 2H), 7.84 (s, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.32-7.25 (m, 1H), 5.73 (bs, 2H), 4.04 (s, 3H), 3.78 (s, 2H), 3.36 (t, J = 6.3 Hz, 2H), 2.96 (bd, J = 11.7 Hz, 2H), 2.07 (t, J = 10.5 Hz, 2H), 1.73 (bd, J = 12.5 Hz, 2H), 1.68-1.58 (m, 1H), 1.45-1.34 (m, 2H);
Mass data (APCI, Pos.): m/z 492 (M + H)+.
実施例234:
4−アミノ−5−シアノ−N2−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピリジン−2,6−ジカルボキサアミド
1H NMR (DMSO-d6): d 10.60 (s, 1H), 8.72 (s, 1H), 8.61 (d, J = 3.9 Hz, 1H), 8.57 (t, J = 6.3 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.95 (dt, J = 7.8, 1.6 Hz, 1H), 7.78 (s, 1H), 7.73 (bs, 2H), 7.50 (s, 1H), 7.48-7.45 (m, 1H), 3.73 (s, 2H), 3.22-3.19 (m, 2H), 2.87 (d, J = 11.0 Hz, 2H), 1.97 (t, J = 11.0 Hz, 2H), 1.64-1.56 (m, 3H), 1.24-1.15 (m, 2H);
Mass data (ESI, Pos.): m/z 499 (M + Na)+.
実施例235:
tert−ブチル (1−(シアノ(2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチルカルバメート
1H NMR (CDCl3): d 8.61 (d, J = 4.7 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.82 (dt, J = 7.8, 1.6 Hz, 1H), 5.02 (s, 1H), 4.57 (bs, 1H), 3.05-2.99 (m, 3H), 2.81-2.77 (m, 1H), 2.56 (dt, J = 11.7, 3.1 Hz, 1H), 2.19 (dt, J = 11.7, 3.1 Hz, 1H), 1.83-1.78 (m, 1H), 1.71-1.66 (m, 1H), 1.54-1.51 (m, 1H), 1.44 (s, 9H), 1.42-1.36 (m, 1H), 1.27-1.17 (m, 1H);
Mass data (APCI, Pos.): m/z 414 (M + Na)+.
実施例236:
2−(4−(アミノメチル)ピペリジン−1−イル)−2−(2−(ピリジン−2−イル)チアゾール−5−イル)アセトニトリル
2時間撹拌した後、反応液をテトラヒドロフランで洗浄して、ろ過をして、濃縮して、さらに精製しなかった。
4−アミノ−5−シアノ−N−((1−(シアノ(2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミド
1H NMR (CDCl3): d 8.61 (d, J = 4.7 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.84-7.78 (m, 2H), 7.37-7.34 (m, 1H), 7.18 (s, 1H), 5.08 (s, 2H), 5.03 (s, 1H), 4.44 (q, J = 7.0 Hz, 2H), 3.41-3.30 (m, 2H), 3.04-3.01 (m, 1H), 2.82-2.80 (m, 1H), 2.61-2.56 (m, 1H), 2.24-2.19 (m, 1H), 1.86-1.83 (m, 1H), 1.75-1.66 (m, 2H), 1.50-1.42 (obs, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.36-1.26 (m, 1H);
Mass data (ESI, Pos.): m/z 476 (M - CN)+.
実施例238:
2−アミノ−6−クロロ−5−ニトロニコチン酸
1H NMR (d6-DMSO): d 13.4 (br s, 1H), 8.71 (br s, 1H), 8.70 (s, 1H), 8.46 (br s, 1H);
Mass data (ESI, Neg.): m/z 216 (M - H)-.
実施例239:
2−アミノ−6−シアノ−5−ニトロニコチン酸
1H NMR (d6-DMSO): d 8.97 (br s, 1H), 8.70 (s, 1H), 8.39 (br s, 1H);
Mass data (ESI, Neg.): m/z 207 (M - H)-.
実施例240:
2,5−ジアミノ−6−シアノニコチン酸
1H NMR (d6-DMSO): d 9.4-8.2 (br m, 3H), 7.78 (s, 1H), 5.40 (br s, 2H).
実施例241:
6−アミノ−5−シアノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)イミダゾ[1,2−a]ピリジン−8−カルボキサアミド
1H NMR (CDCl3): d 10.33 (br t, J = 4.7 Hz, 1H), 8.60 (d, J = 3.9 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.80 - 7.76 (m, 2H), 7.74 (s, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.30 (dd, J = 4.7, 7.8 Hz, 1H), 4.61(s, 2H), 3.78 (s, 2H), 3.45 (t, J = 6.26 Hz, 2H), 3.01-2.95 (m, 2H), 2.14-2.05 (m, 2H), 1.85-1.38 (m, 5H);
Mass data (ESI, Pos.): m/z 495 (M + Na)+.
実施例242:
6−アミノ−5−シアノ−2−エチル−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)イミダゾ[1,2−a]ピリジン−8−カルボキサアミド
1H NMR (CDCl3): d 10.46 (m, 1H), 8.60 (d, J = 3.1 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.80 - 7.76 (m, 2H), 7.68 (s, 1H), 7.66 (s, 1H), 7.30 (dd, J = 4.7, 8.6 Hz, 1H), 4.45 (s, 2H), 3.78 (s, 2H), 3.47-3.27 (m, 2H), 3.04-2.77 (m, 4H), 2.14-2.03 (m, 2H), 1.86-1.30 (m, 8H);
Mass data (APCI, Pos.): m/z 501 (M + H)+.
実施例243:
tert−ブチル (1−(5−(ピリジン−2−イル)チオフェン−2−イルスルホニル)ピペリジン−4−イル)メチルカルバメート
1H NMR (DMSO-d6): d 8.58 (d, J = 5.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.95-7.90 (m, 2H), 7.63 (d, J = 4.0 Hz, 1H), 7.40 (dd, J = 4.9, 7.5 Hz, 1H), 6.88 (t, J = 5.8 Hz, 1H), 3.63 (d, J = 11.5 Hz, 2H), 2.79 (t, J = 6.1 Hz, 2H), 2.36 (t, J = 10.5 Hz, 2H), 1.70 (d, J = 10.8 Hz, 2H), 1.33-1.30 (m, 10H), 1.2-1.13 (m, 2H);
Mass data (APCI, Pos.): m/z 438 (M + H)+.
実施例244:
(1−(5−(ピリジン−2−イル)チオフェン−2−イルスルホニル)ピペリジン−4−イル)メタンアミン 二塩酸塩
Mass data (APCI, Pos.): m/z 338 (M + H)+.
実施例245:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(5−(ピリジン−2−イル)チオフェン−2−イルスルホニル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): d 8.58 (d, J = 4.6 Hz, 1H), 8.49 (t, J = 6.2 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.95-7.90 (m, 2H), 7.63 (d, J = 3.9 Hz, 1H), 7.45-7.39 (m, 1H), 7.31 (br, 2H), 7.01 (s, 1H), 4.45 (q, J = 7.0 Hz, 2H), 3.64 (d, J = 11.6 Hz, 2H), 3.14 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 10.7 Hz, 2H), 1.73 (d, J = 13.7 Hz, 2H), 1.60-1.56 (m, 1H), 1.29 (t, J = 7.0 Hz, 3H), 1.26-1.20 (m, 2H);
Mass data (APCI, Pos.): m/z 527 (M + H)+.
実施例246:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((3−(ピリジン−2−イル)−1,2,4−オキサジアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CD3OD): d 8.71 (d, J = 4.66 Hz, 1H), 8.18 (d, J = 7.86 Hz, 1H), 8.02 (d, J = 7.77 Hz, 1H), 7.98 (br, 1H), 7.60-7.57 (m, 1H), 7.30 (br, 2H), 7.08 (s, 1H), 4.48 (q, J = 7.07 Hz, 2H), 4.00 (s, 1H), 3.07-3.03 (m, 2H), 2.30 (t, J = 10.78 Hz, 2H), 1.76 (d, J = 13.16 Hz, 2H), 1.69-1.63 (m, 1H), 1.44-1.28 (m, 5H);
Mass data (APCI, Pos.): m/z 463 (M + H)+.
実施例247:
5−(クロロメチル)−3−(ピリジン−2−イル)−1,2,4−オキサジアゾール
1H NMR (DMSO-d6): d 8.78 (d, J = 4.7 Hz, 1H), 8.11-8.02 (m, 2H), 7.65-7.62 (m, 1H), 5.21 (s, 2H);
Mass data (APCI, Pos.): m/z 196 (M + H)+.
実施例248:
1−ベンジル−4−ヒドロキシピペリジン−4−カルボニトリル
1H NMR (DMSO-d6): d 7.30 (m, 5H), 6.56 (br, 1H), 3.38 (q, J = 7.0 Hz, 2H), 2.62-2.59 (m, 2H), 2.26-2.21 (m, 2H), 1.99-194 (m, 2H), 1.76-1.70 (m, 2H).
実施例249:
4−(アミノメチル)−1−ベンジルピペリジン−4−オール
1H NMR (DMSO-d6): d 7.29 (m, 5H), 6.56 (br, 1H), 4.52 (br, 1H), 3.93 (br, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.44 (m, 2H), 2.65-2.62 (m, 2H), 2.44-2.41 (m, 2H), 2.31-2.25 (m, 2H), 2.03-1.99 (m, 2H), 1.71-1.66 (m, 1H), 1.43-1.36 (m, 6H);
Mass data (APCI, Pos.): m/z 221 (M + H)+.
実施例250:
tert−ブチル (1−ベンジル−4−ヒドロキシピペリジン−4−イル)メチルカーバメート
1H NMR (DMSO-d6): d 7.29 (m, 5H), 6.56 (br, 1H), 4.16 (br, 1H), 4.09 (q, J = 5.3 Hz, 2H), 2.90 (d, J = 6.1 Hz, 2H), 2.45-2.23 (m, 4H), 2.62-2.59 (m, 2H), 1.38 (s, 9H), 1.65-1.31 (m, 13H);
Mass data (APCI, Pos.): m/z 321 (M + H)+.
実施例251:
tert−ブチル (4−ヒドロキシピペリジン−4−イル) メチルカーバメート
1H NMR (DMSO-d6): δ 6.52 (br, 1H), 4.17 (br, 1H), 2.75-2.69 (m, 2H), 2.62-2.59 (m, 2H), 1.38 (s, 9H), 1.34-1.25 (m, 4H);
マスデータ (APCI, Pos.): m/z 231 (M + H)+.
実施例252:
tert−ブチル (4−ヒドロキシ−1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチルカーバメート
1H NMR (DMSO-d6): δ 8.61 (d, J = 4.8 Hz, 1H), 8.109 (d, J = 7.9 Hz, 1H), 7.97-7.92 (m, 1H), 7.79 (s, 1H), 7.48-7.44 (m, 1H), 6.58 (br, 1H), 4.19 (br, 1H), 3.73 (s, 1H), 2.91 (d, J = 6.1 Hz, 2H), 2.58 (m, 2H), 2.34 (t, J = 10.0 Hz, 2H), 1.51-1.34 (m, 1H), 1.44-1.28 (m, 12H);
マスデータ (APCI, Pos.): m/z 405 (M + H)+.
実施例253:
4−(アミノメチル)−1−{[2−(2−ピリジニル)−1,3−チアゾール−5−イル]メチル}−4−ピペリジノール ビス(トリフルオロアセテート)
マスデータ(APCI, Pos.): m/z 305 (M + H)+.
実施例254:
4−アミノ−5−シアノ−6−エトキシ−N−((4−ヒドロキシ−1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 8.61 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 6.1 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.94 (td, J = 1.7, 7.7 Hz, 1H), 7.79 (s, 1H), 7.48-7.44 (m, 1H), 7.34 (br, 2H), 7.06 (s, 1H), 4.59 (br, 1H), 4.42 (q, J = 7.0 Hz, 2H), 3.75 (s, 1H), 3.28 (d, J = 5.8 Hz, 2H), 2.56 (m, 2H), 2.42-2.37 (m, 2H), 1.52-1.46 (m, 4H), 1.33 (t, J = 7.0 Hz, 2H);
マスデータ (APCI, Pos.): m/z 494 (M + H)+.
実施例255:
tert−ブチル 1−オキサ−6−アザスピロ[2.5]オクタン−6−カルボキシレート
1H NMR (DMSO-d6): δ 3.53-3.47 (m, 2H), 3.41-3.34 (m, 2H), 2.65 (s, 1H), 1.67-1.61 (m, 2H), 1.41-1.35 (m, 11H).
実施例256:
tert−ブチル 4−(アジドメチル)−4−ヒドロキシピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 4.85 (br, 1H), 3.64 (d, J = 12.9 Hz, 2H), 3.17 (s, 2H), 3.05 (br, 2H), 1.51-1.32 (m, 13H).
実施例257:
tert−ブチル 4−(アジドメチル)−4−メトキシピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 3.62 (br, 2H), 3.37 (s, 3H), 3.16 (s, 2H), 2.95 (br, 2H), 1.70 (d, J = 12.7 Hz, 2H), 1.41-1.32 (m, 11H);
マスデータ (APCI, Pos.): m/z 171 (M + H - Boc)+.
実施例258:
tert−ブチル 4−(アミノメチル)−4−メトキシピペリジン−1−カルボキシレート
マスデータ (APCI, Pos.): m/z 245 (M + H)+.
実施例259:
tert−ブチル 4−((4−アミノ−5−シアノ−6−エトキシピコリンアミド)メチル)−4−メトキシピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 8.11 (t, J = 6.3 Hz, 1H), 7.36 (br, 2H), 7.06 (s, 1H), 4.43 (q, J = 7.0 Hz, 2H), 3.64 (d, J = 12.7 Hz, 2H), 3.38 (d, J = 6.3 Hz, 2H), 3.18 (s, 3H), 2.96 (br, 2H), 1.65 (d, J = 13.3 Hz, 2H), 1.38-1.32 (m, 14H);
マスデータ (APCI, Pos.): m/z 434 (M + H)+.
実施例260:
4−アミノ−5−シアノ−6−エトキシ−N−((4−メトキシピペリジン−4−イル)メチル)ピコリンアミド
マスデータ (APCI, Pos.): m/z 334 (M + H)+.
実施例261:
4−アミノ−5−シアノ−6−エトキシ−N−((4−メトキシ−1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 8.61 (d, J = 4.6 Hz, 1H), 8.1-8.06 (m, 2H), 7.97-7.92 (m, 1H), 7.70 (s, 1H), 7.49-7.45 (m, 1H), 7.36 (br, 1H), 7.05 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 3.37 (d, J = 6.2 Hz, 2H), 3.14 (s, 3H), 2.58-2.54 (m, 2H), 2.33-2.25 (m, 2H), 1.71-1.68 (m, H), 1.53-1.46 (m, 2H), 1.73 (t, J = 7.0 Hz, 3H);
マスデータ (APCI, Pos.): m/z 508 (M + H)+.
実施例262:
1−ベンジル−4−(ヒドロキシメチル)ピペリジン−3−オール
シリカゲルのカラムクロマトグラフィー(ジクロロメタン中、1−10%のエタノール)で精製することで、以下の物性値を有する標題化合物(2.66 g、シス−異性体; 2.28 g、トランス−異性体)を得た。
(シス)−異性体
1H NMR (DMSO-d6): δ 7.32-7.24 (m, 5H), 4.27 (t, J = 5.3 Hz, 1H), 3.94 (d, J = 6.9 Hz, 1H), 3.73-3.69 (m, 1H), 3.49-3.46 (m, 1H), 3.32 (s, 2H), 3.28-3.23 (m, 1H), 2.72-2.67 (m, 2H), 2.04 (d, J = 10.3 Hz, 1H), 1.97-1.92 (m, 1H), 1.56-1.35 (m, 3H).
(トランス)−異性体
1H NMR (DMSO-d6): δ 7.31-7.23 (m, 5H), 4.27 (t, J = 5.3 Hz, 1H), 4.55 (d, J = 5.2 Hz, 1H), 4.32 (t, J = 5.2 Hz, 1H), 3.64-3.59 (m, 1H), 3.49 (d, J = 13.1 Hz, 1H), 3.38 (d, J = 13.1 Hz, 1H), 3.26-3.20 (m, 2H), 2.83 (dd, J = 3.5, 10.40 Hz, 1H), 2.75 (d, J = 10.9 Hz, 2H), 1.82 (t, J = 11.2 Hz, 1H), 1.69-1.61 (m, 1H), 1.24-1.18 (m, 3H).
マスデータ (APCI, Pos.): m/z 508 (M + H)+.
実施例263:
(トランス)−4−(ヒドロキシメチル) ピペリジン−3−オール
1H NMR (DMSO-d6): δ 4.53 (br, 1H), 4.33 (br, 1H), 3.59 (dd, J = 10.3, 4.4 Hz, 1H), 3.44 (q, J = 7.0 Hz, 1H), 3.32 (dd, J = 10.0 Hz, 1H), 3.17-3.10 (m, 1H), 2.92 (dd, J = 4.5, 11.5 Hz, 1H), 2.83-2.78 (m, 1H), 2.32 (td, J = 2.7, 12.1 Hz, 1H), 2.15 (dd, J = 10.0, 11.5 Hz, 1H), 1.64 (ddd, J = 2.6, 6.3, 13.1 Hz, 1H), 1.32-1.23 (m, 1H), 1.09-1.02 (m, 1H);
マスデータ (APCI, Pos.): m/z 132 (M + H)+.
実施例264:
(トランス)−tert−ブチル 3−ヒドロキシ−4−(ヒドロキシメチル)ピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 4.85 (d, J = 5.0 Hz, 1H), 4.37 (t, J = 5.2 Hz, 1H), 3.97-3.84 (m, 2H), 3.62-3.57 (m, 1H), 3.36-3.34 (m, 2H), 3.14-3.03 (m, 1H), 1.71-1.65 (m, 1H), 1.38-1.31 (m, 11H), 1.15-1.05 (m, 1H);
マスデータ (APCI, Pos.): m/z 132 (M + H - Boc)+.
実施例265:
(トランス)−tert−ブチル 4−(アジドメチル)−3−ヒドロキシピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 5.11 (d, J = 5.3 Hz, 1H), 4.06-3.83 (m, 2H) 3.58 (dd, J = 3.4, 12.1 Hz, 1H), 3.38-3.34 (m, 2H), 3.14-3.07 (m, 1H), 1.71-1.65 (m, 1H), 1.54-1.46 (m, 1H), 1.39 (s, 11H), 1.23-1.10 (m, 1H).
実施例266:
(トランス)−tert−ブチル 4−(アミノメチル)−3−ヒドロキシピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 5.76 (s, 1H), 3.95-3.83 (m, 2H), 3.20-3.1 (m, 3H), 2.72-2.58 (m, 2H), 2.43-2.33 (m, 1H), 1.76-1.54 (m, 1H), 1.38 (s, 9H), 1.32-0.93 (m, 2H);
マスデータ (APCI, Pos.): m/z 231 (M + H)+.
実施例267:
(トランス)−tert−ブチル 4−((4−アミノ−5−シアノ−6−エトキシピコリンアミド)メチル)−3−ヒドロキシピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 6.79 (br, 1H), 7.31 (br, 2H), 7.01 (s, 1H), 5.33 (d, J = 4.5 Hz, 1H), 4.45-4.40 (m, 3H), 4.03-3.81 (m, 2H), 3.42-3.36 (m, 2H), 3.27-3.16 (m, 2H), 2.45-2.38 (m, 2H), 2.43-2.33 (m, 1H), 1.76-1.54 (m, 1H), 1.38 (s, 9H), 1.33-1.29 (m, 2H), 1.09 (t, J = 7.0 Hz, 3H);
マスデータ (APCI, Pos.): m/z 420 (M + H)+.
実施例268:
4−アミノ−5−シアノ−6−エトキシ−N−(((トランス)−3−ヒドロキシピペリジン−4−イル)メチル)ピコリンアミド
マスデータ (APCI, Pos.): m/z 320 (M + H)+.
実施例269:
4−アミノ−5−シアノ−6−エトキシ−N−(((トランス)−3−ヒドロキシ−1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 8.84 (br, 1H), 8.61 (d, J = 4.2 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.95 (td, J = 1.7, 7.7 Hz, 1H), 7.80 (s, 1H), 7.47 (ddd, J = 1.1, 4.8, 7.5 Hz, 1H), 7.30 (br, 2H), 7.04 (s, 1H), 5.09 (d, J = 4.7 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 3.82 (d, J = 14.2 Hz, 1H), 3.73 (d, J = 14.2 Hz, 1H), 3.48-3.40 (m, 1H), 3.29-3.21 (m, 2H), 2.96-2.82 (m, 2H), 1.97-1.92 (m, 1H), 1.78 (t, J = 10.1 Hz, 1H), 1.62 (d, J = 9.7 Hz, 1H), 1.41-1.31 (m, 1H), 1.29 (t, J = 7.0 Hz, 3H), 1.25-1.21 (m, 1H);
マスデータ (APCI, Pos.): m/z 494 (M + H)+.
実施例270:
4−アミノ−5−シアノ−6−エトキシ−N−(((シス)−3−ヒドロキシ−1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CD3OD): δ 8.62-8.58 (m, 2H), 8.09 (d, J = 7.9 Hz, 1H), 7.95 (td, J = 1.7, 7.8 Hz, 1H), 7.80 (s, 1H), 7.49-7.45 (m, 1H), 7.31 (br, 2H), 7.04 (s, 1H), 4.50 (d, J = 5.6 Hz, 1H), 4.45 (q, J = 7.0 Hz, 2H), 3.76 (br, 2H), 3.72-3.68 (m, 1H), 3.28-3.21 (m, 2H), 2.79-2.73 (m, 2H), 2.22-2.18 (m, 1H), 2.09 (t, J = 9.4 Hz, 1H), 1.71-1.58 (m, 1H), 1.40-1.32 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H);
マスデータ (APCI, Pos.): m/z 494 (M + H)+.
実施例271:
ジメチル 2−(フェニルアミノ)マレート
1H NMR (DMSO-d6): δ 9.61 (br, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.28 (s, 1H), 3.67 (s, 6H);
マスデータ (APCI, Pos.): m/z 236 (M + H)+.
実施例272:
メチル 4−オキソ−1,4−ジヒドロキノリン−2−カルボキシレート
1H NMR (CD3OD): δ 8.24 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 6.94 (s, 1H), 5.49 (s, 1H), 4.04 (s, 3H);
マスデータ (APCI, Neg.): m/z 202 (M - H)-.
実施例273:
メチル 4−アジドキノリン−2−カルボキシレート
1H NMR (CD3OD): d 8.18 (dd, J = 8.3, 4.7 Hz, 1H), 7.99 (s, 1H), 7.88 (m, 1H), 7.72 (m, 1H), 7.40-7.16 (m, 1H), 4.07 (s, 3H);
マスデータ (APCI, Pos.): m/z 229 (M + H)+.
実施例274:
メチル 4−アミノキノリン−2−カルボキシレート
1H NMR (DMSO-d6): δ 8.20 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 5.46 (br, 2H), 3.86 (s, 3H);
マスデータ (APCI, Pos.): m/z 203 (M + H)+.
実施例275:
4−アミノキノリン−2−カルボキシリック アシッド
マスデータ (APCI, Neg.): m/z 187 (M - H)-.
実施例276:
4−アミノ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)キノリン−2−カルボキサアミド
1H NMR (CD3OD): δ 8.07 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.84-7.81 (m, 2H), 7.66 (t, J = 7.7 Hz, 1H), 7.48-7.41 (m, 4H), 7.30 (s, 1H), 6.78 (s, 1H), 3.77 (s, 2H), 3.35 (d, J = 6.8 Hz, 2H), 3.01 (d, J = 11.5 Hz, 2H), 2.19 (t, J = 10.8 Hz, 2H), 1.82 (d, J = 12.4 Hz, 2H), 1.71-1.67 (m, 1H), 1.47-1.38 (m, 2H);
マスデータ (APCI, Pos.): m/z 442 (M + H)+.
実施例277:
4−アミノ−8−メトキシ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)キノリン−2−カルボキサアミド
1H NMR (CD3OD): δ 7.84-7.81 (m, 2H), 7.64(d, J = 8.6 Hz, 1H), 7.46-7.38 (m, 5H), 7.18 (d, J = 7.7 Hz, 1H), 6.79 (s, 1H), 4.07 (s, 3H), 3.78 (s, 2H), 3.35 (d, J = 6.8 Hz, 2H), 3.01 (d, J = 11.7 Hz, 2H), 2.21 (t, J = 11.7 Hz, 2H), 1.85 (d, J = 12.1 Hz, 2H), 1.74-1.67 (m, 1H), 1.47-1.38 (m, 2H);
マスデータ (APCI, Pos.): m/z 442 (M + H)+.
実施例278:
2−ブロモ−6−エトキシピリジン
1H NMR (CDCl3): δ 7.40 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).
実施例279:
2−ブロモ−6−エトキシ−3−ニトロピリジン
1H NMR (DMSO-d6): δ 8.41 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H);
マスデータ (APCI, Pos.): m/z 245 (M + H)+.
実施例280:
6−エトキシ−3−ニトロピコリノニトリル
1H NMR (DMSO-d6): δ 8.62 (d, J = 9.2 Hz, 1H), 7.36 (d, J = 9.2 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H).
実施例281:
3−アミノ−6−エトキシピコリノニトリル
1H NMR (DMSO-d6): δ 7.26 (d, J = 9.1 Hz, 1H), 6.89 (d, J = 9.0 Hz, 1H), 5.84 (br, 2H), 4.14 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H);
マスデータ (APCI, Pos.): m/z 164 (M + H)+.
施例282:
3−アミノ−6−エトキシピコリン酸
1H NMR (DMSO-d6): δ 8.16 (br, 2H), 7.26 (d, J = 8.9 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H);
マスデータ (APCI, Neg.): m/z 181 (M - H)-.
実施例283:
3−アミノ−6−エトキシ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 8.22 (t, J = 6.2 Hz, 1H), 7.89-7.86 (m, 2H), 7.52-7.50 (m, 3H), 7.18 (d, J = 8.8 Hz, 1H), 6.95 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.41 (br, 2H), 4.24 (q, J = 7.0 Hz, 2H), 3.70 (s, 2H), 3.16-3.14 (m, 2H), 2.87 (s, J = 11.2 Hz, 2H), 2.03 (t, J = 10.7 Hz, 2H), 1.63 (d, J = 13.3 Hz, 2H), 1.54-1.49 (m, 1H), 1.29-1.20 (m, 5H);
マスデータ (APCI, Pos.): m/z 436 (M + H)+.
実施例284:
2−エトキシニコチン酸
1H NMR (DMSO-d6): δ 12.94 (br, 1H), 8.31 (dd, J = 1.6, 4.6 Hz, 1H), 8.07 (m, 1H), 7.05 (dd, J = 4.9, 7.4 Hz, 1H), 4.39 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H);
マスデータ (APCI, Pos.): m/z 168 (M + H)+.
実施例285:
エチル 2−エトキシニコチネート
1H NMR (DMSO-d6): d 8.34 (dd, J = 1.7, 4.8 Hz, 1H), 8.09 (dd, J = 1.7, 7.6 Hz, 1H), 7.08 (dd, J = 4.9, 7.4 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 5.5 Hz, 3H), 1.29 (t, J= 5.6 Hz, 3H);
マスデータ (APCI, Pos.): m/z 196 (M + H)+.
実施例286:
エチル 2−エトキシ−5−ニコチネート
1H NMR (DMSO-d6): δ 9.23 (s, 1H), 8.75 (s, 1H), 4.55 (q, J = 7.0 Hz, 2H), 4.33 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H), 1.32 (t, J= 7.1 Hz, 3H).
実施例287:
エチル 5−アミノ−2−エトキシニコチネート
1H NMR (DMSO-d6): δ 7.69 (s, 1H), 7.40 (s, 1H), 4.99 (br, 2H), 4.26-4.19 (m, 4H), 1.29-1.24 (m, 6H);
マスデータ (APCI, Pos.): m/z 211 (M + H)+.
実施例288:
5−アミノ−2−エトキシニコチン酸
マスデータ (APCI, Neg.): m/z 181 (M - H)-.
実施例289:
5−アミノ−2−エトキシ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ニコチンアミド
1H NMR (CD3OD): δ 7.85-7.81 (m, 2H), 7.72 (dd, J = 13.8, 2.7 Hz, 1H), 7.48-7.46 (m, 3H), 6.78 (s, 1H), 4.41 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H), 3.35 (s, 2H), 3.01 (d, J = 11.6 Hz, 2H), 2.20 (t, J = 11.6 Hz, 2H), 1.81 (d, J = 12.6 Hz, 2H), 1.65-1.61 (m, 1H), 1.45-1.35 (m, 5H);
マスデータ (APCI, Pos.): m/z 436 (M + H)+.
実施例290:
5−アミノ−2−エトキシ−6−メチル−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ニコチンアミド
1H NMR (CD3OD): δ 8.46 (br, 1H), 7.84-7.82 (m, 2H), 7.67 (s, 1H), 7.48-7.46 (m, 3H), 4.45 (q, J = 7.0 Hz, 2H), 3.81 (s, 2H), 3.35 (s, 2H), 3.04 (d, J = 11.5 Hz, 2H), 2.33 (s, 3H), 2.23 (t, J = 11.5 Hz, 2H), 1.81 (d, J = 12.6 Hz, 2H), 1.69-1.61 (m, 1H), 1.46-1.37 (m, 5H);
マスデータ (APCI, Pos.): m/z 450 (M + H)+.
実施例291:
エチル 5−アミノ−6−クロロ−2−エトキシニコチネート
1H NMR (DMSO-d6): δ 7.64 (s, 1H), 5.21 (br, 2H), 4.27-4.18 (m, 4H), 1.28 (t, J = 7.0 Hz, 3H);
マスデータ (APCI, Pos.): m/z 245 (M + H)+.
実施例292:
5−アミノ−6−クロロ−2−エトキシニコチン酸
1H NMR (DMSO-d6): δ 12.82 (br, 1H), 7.63 (s, 1H), 5.16 (br, 2H), 4.21 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H);
マスデータ (APCI, Neg.): m/z 215 (M - H)-.
実施例293:
5−アミノ−6−クロロ−2−エトキシ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ニコチンアミド
1H NMR (CD3OD): δ 7.83-7.81 (m, 2H), 7.76 (s, 1H), 7.48-7.46 (m, 3H), 6.78 (s, 1H), 4.40 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H), 3.31 (s, 2H), 3.01 (d, J = 11.6 Hz, 2H), 2.19 (t, J = 10.8 Hz, 2H), 1.79 (d, J = 12.5 Hz, 2H), 1.65-1.61 (m, 1H), 1.43-1.37 (m, 5H);
マスデータ (APCI, Pos.): m/z 470 (M + H)+.
実施例294:
2,6−ジエトキシニコチン酸
1H NMR (DMSO-d6): δ 12.33 (br, 1H), 8.06 (d, J = 8.3 Hz, 1H), 6.38 (d, J = 8.3 Hz, 1H), 4.40 (q, 7.0 Hz, 2H), 4.21 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H).
実施例295:
エチル 2,6−ジエトキシニコチネート
1H NMR (DMSO-d6): δ 8.07 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 8.4 Hz, 1H), 4.42-4.33 (m, 4H), 4.21 (q, J = 7.1 Hz, 2H), 1.35-1.31 (m, 6H), 1.27 (t, J = 7.1 Hz, 3H);
マスデータ (APCI, Pos.): m/z 240 (M + H)+.
実施例296:
エチル 2,6−ジエトキ−5−ニトロニコチネート
1H NMR (DMSO-d6): δ 8.78 (s, 1H), 4.59 (q, J = 7.0 Hz, 2H), 4.52 (q, J = 7.0 Hz, 2H), 4.27 (q, 7.1 Hz, 2H), 1.35-1.31 (m, 6H), 1.29 (t, 7.1 Hz, 3H).
実施例297:
エチル 5−アミノ−2,6−ジエトキシニコチネート
1H NMR (DMSO-d6): δ 7.42 (s, 1H), 4.51 (br, 2H), 4.38 (q, J = 7.0 Hz, 2H), 4.27 (q, J = 7.0 Hz, 2H), 4.18 (q, 7.1 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 6.6 Hz, 3H), 1.26 (t, 6.9 Hz, 3H);
マスデータ (APCI, Pos.): m/z 255 (M + H)+.
実施例298:
5−アミノ−2,6−ジエトキシニコチン酸
1H NMR (DMSO-d6): δ 12.08 (br, 1H), 7.43 (s, 1H), 4.63 (br, 2H), 4.38 (q, J = 7.0 Hz, 2H), 4.29 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H);
マスデータ (APCI, Neg.): m/z 225 (M - H)-.
実施例299:
5−アミノ−2,6−ジエトキシ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ニコチンアミド
1H NMR (CD3OD): δ 8.33 (br, 1H), 7.84-7.81 (m, 2H), 7.65 (s, 1H), 7.49-7.46 (m, 3H), 6.80 (s, 1H), 4.46 (q, J = 7.2 Hz, 4H), 3.83 (s, 2H), 3.31 (s, 2H), 3.04 (d, J = 11.5 Hz, 2H), 2.25 (t, J = 10.9 Hz, 2H), 1.81 (d, J = 13.0 Hz, 2H), 1.65-1.59 (m, 1H), 1.44-1.40 (m, 5H);
マスデータ (APCI, Pos.): m/z 480 (M + H)+.
実施例300:
4−アミノ−6−エトキシ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 7.84-7.81 (m, 2H), 7.48-7.45 (m, 3H), 6.97 (s, 1H), 6.78 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.77 (s, 2H), 3.34 (s, 2H), 3.0 (d, J = 11.3 Hz, 2H), 2.18 (t, J = 11.3 Hz, 2H), 1.77 (d, J = 13.4 Hz, 2H), 1.79-1.63 (m, 1H), 1.40-1.29 (m, 5H).
実施例301:
(Z)−tert−ブチル 4−(3−(2−ニトロフェニル)−3−オキソプロプ−1−エニル)ピペリジン−1−カルボキシレート
1H NMR (CDCl3): δ 8.13-8.10 (m, 1H), 7.75-7.71 (m, 1H), 7.65-7.60 (m, 1H), 7.45-7.42 (m, 1H), 6.39-6.37 (m, 2H), 2.78-2.71 (m, 2H), 2.37-2.28 (m, 1H), 1.72-1.68 (m, 2H), 1.46-1.44 (m, 11H), 1.36-1.25 (m, 2H);
マスデータ (APCI, Pos.): m/z 361 (M + H)+.
実施例302:
tert−ブチル 4−(3−(2−アミノフェニル)−3−オキソプロピル)ピペリジン−1−カルボキシレート
1H NMR (CDCl3): δ 7.74-7.72 (m, 1H), 7.28-7.24 (m, 1H), 6.67-6.62 (m, 2H), 6.27 (br s, 2H), 4.15-4.09 (m, 2H), 2.96 (t, J = 7.0 Hz, 3H), 2.72-2.65 (m, 2H), 1.73-1.65 (m, 4H), 1.51-1.44 (m, 10H), 1.20-1.09 (m, 2H);
マスデータ (APCI, Pos.): m/z 333 (M + H)+.
実施例303:
tert−ブチル 4−(3−オキソ−3−(2−(フェニルアミノ)フェニル)プロピル)ピペリジン−1−カルボキシレート
1H NMR (CDCl3): δ 10.56 (br s, 1H), 7.84-7.82 (m, 1H), 7.37-7.24 (m, 6H), 7.12-7.08 (m, 1H), 6.75-6.71 (m, 1H), 4.10 (br s, 2H), 3.03 (t, J = 7.6 Hz, 2H), 2.73-2.66 (m, 2H), 1.74-1.68 (m, 4H), 1.54-1.48 (m, 1H), 1.46 (s, 9H), 1.21-1.11 (m, 2H);
マスデータ (APCI, Pos.): m/z 409 (M + H)+.
実施例304:
tert−ブチル 4−(3−(2−(2−メトキシ−2−オキソ−N−フェニルアセトアミド)フェニル)−3−オキソプロピル)ピペリジン−1−カルボキシレート
マスデータ (APCI, Pos.): m/z 495 (M + H)+.
実施例305:
メチル 3−((1−(tert−ブトキシカルボニル)ピペリジン−4−イル)メチル)−4−オキソ−1−フェニル−1,4−ジヒドロキノリン−2−カルボキシレート
1H NMR (CDCl3): δ 8.47-8.44 (m, 1H), 7.58-7.55 (m, 3H), 7.49-7.45 (m, 1H), 7.40-7.34 (m, 3H), 6.81-6.78 (m, 1H), 4.07 (br s, 2H), 3.48 (s, 3H), 2.79-2.62 (m, 2H), 2.47 (br s, 2H), 2.04-1.97 (m, 1H), 1.70-1.67 (m, 2H), 1.44 (s, 9H), 1.19-1.08 (m, 2H);
マスデータ (APCI, Pos.): m/z 477 (M + H)+.
実施例306:
メチル 4−オキソ−1−フェニル−3−(ピペリジン−4−イルメチル)−1,4−ジヒドロキノリン−2−カルボキシレート 塩酸塩
マスデータ (APCI, Pos.): m/z 377 (M + H (free base))+.
実施例307:
メチル 4−オキソ−1−フェニル−3−((1−((3−(ピリジン−2−イル)イソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−1,4−ジヒドロキノリン−2−カルボキシレート
1H NMR (CDCl3): δ 8.68-8.67 (m, 1H), 8.45-8.44 (m, 1H), 8.06-8.04 (m, 1H), 7.80-7.76 (m, 1H), 7.56-7.54 (m, 3H), 7.47-7.44 (m, 1H), 7.36-7.31 (m, 4H), 6.79-6.77 (m, 2H), 3.73 (s, 2H), 3.47 (s, 3H), 2.95-2.92 (m, 2H), 2.47 (d, J = 7.0 Hz, 2H), 2.13-2.08 (m, 2H), 1.95-1.86 (m, 1H), 1.74-1.71 (m, 2H), 1.34-1.27 (m, 2H);
マスデータ (APCI, Pos.): m/z 535 (M + H)+.
実施例308:
1−(2−アミノフェニル)−3−(ピペリジン−4−イル)プロパン−1−オン 二塩酸塩
1H NMR (DMSO-d6): δ 9.20 (s, 1H), 8.78 (s, 1H), 7.80-7.78 (m, 1H), 7.28-7.24 (m, 1H), 6.82-6.80 (m, 1H), 6.61-6.58 (m, 1H), 6.35 (s, 2H), 3.23-3.17 (m, 2H), 2.97-2.95 (m, 2H), 2.82-2.78 (m, 2H), 1.85-1.82 (m, 2H), 1.56-1.54 (2H), 1.37-1.33 (m, 2H);
マスデータ (APCI, Pos.): m/z 233 (M + (free base))+.
実施例309:
1−(2−アミノフェニル)−3−(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)プロパン−1−オン
1H NMR (CDCl3): δ 8.61-8.60 (m, 1H), 8.15-8.13 (m, 1H), 7.80-7.72 (m, 2H), 7.68 (s, 1H), 7.31-7.23 (m, 2H), 6.66-6.63 (m, 2H), 6.25 (s, 2H), 3.77 (s, 2H), 2.96-2.92 (m, 4H), 2.05-2.03 (m, 2H), 1.71-1.60 (m, 6H), 1.32-1.28 (m, 1H);
マスデータ (APCI, Pos.): m/z 407 (M + H)+.
実施例310:
1−(2−(フェニルアミノ)フェニル)−3−(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)プロパン−1−オン
1H NMR (CDCl3): δ 10.57 (s, 1H), 8.61-8.60 (m, 1H), 7.84-7.77 (m, 2H), 7.68 (s, 1H), 7.36-7.23 (m, 5H), 7.11-7.08 (m, 1H), 6.74-6.71 (m, 1H), 3.80-3.75 (m, 3H), 3.03-2.94 (m, 4H), 2.63 (s, 2H), 2.18 (s, 2H), 2.08-2.04 (m, 2H), 1.75-1.67 (m, 2H), 1.33-1.25 (m, 4H);
マスデータ (APCI, Pos.): m/z 483 (M + H)+.
実施例311:
2−(ジメチルアミノ)エチル 2−オキソ−2−(フェニル (2−(3−(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)プロパノイル)フェニル)アミノ)アセテート
マスデータ (APCI, Pos.): m/z 626 (M + H)+.
実施例312:
2−(ジメチルアミノ)エチル 4−オキソ−1−フェニル−3−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−1,4−ジヒドロキノリン−2−カルボキシレート
1H NMR (CDCl3): δ 8.59-8.58 (m, 1H), 8.45-8.43 (m, 1H), 8.14-8.12 (m, 1H), 7.79-7.76 (m, 1H), 7.66 (s, 1H), 7.57-7.54 (m, 2H), 7.46-7.39 (m, 3H), 7.35-7.26 (m, 3H), 6.78-6.76 (m, 1H), 3.95 (t, J = 6.1 Hz, 2H), 3.73 (s, 2H), 2.92-2.90 (m, 2H), 2.50 (d, J = 6.9 Hz, 2H), 2.28 (t, J = 6.2Hz, 2H), 2.17 (s, 6H), 2.05-2.02 (m, 2H), 1.72-1.69 (m, 2H), 1.59-1.49 (m, 1H), 1.39-1.32 (m, 2H);
マスデータ (APCI, Pos.): m/z 608 (M + H)+.
実施例313:
2−モルホリノエチル 2−オキソ−2−(フェニル(2−(3−(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)プロパノイル)フェニル)アミノ)アセテート
マスデータ (APCI, Pos.): m/z 668 (M + H)+.
実施例314:
2−モルホリノエチル 4−オキソ−1−フェニル−3−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−1,4−ジヒドロキノリン−2−カルボキシレート
1H NMR (CDCl3): δ 8.59-8.58 (m, 1H), 8.46-8.44 (m, 1H), 8.14-8.12 (m, 1H), 7.78-7.76 (m, 1H), 7.66 (s, 1H), 7.56-7.54 (m, 3H), 7.46-7.44 (m, 1H), 7.40-7.27 (m, 4H), 6.78-6.75 (m, 1H), 3.99-3.97 (m, 2H), 3.73 (s, 2H), 3.68-3.66 (m, 3H), 2.92-2.90 (m, 2H), 2.50-2.49 (m, 2H), 2.40-2.32 (m, 6H), 2.05-2.00 (m, 2H), 1.92-1.85 (m, 1H), 1.72-1.69 (m, 2H), 1.35-1.25 (m, 3H);
マスデータ (APCI, Pos.): m/z 650 (M + H)+.
実施例315:
tert−ブチル 4−(3−(2−(2−(2−(ジメチルアミノ)エトキシ)−2−オキソ−N−フェニルアセトアミド)フェニル)−3−オキソプロピル)ピペリジン−1−カルボキシレート
2−(ジメチルアミノ)エチル 3−((1−(tert−ブトキシカルボニル)ピペリジン−4−イル)メチル)−4−オキソ−1−フェニル−1,4−ジヒドロキノリン−2−カルボキシレート
マスデータ (APCI, Pos.): m/z 534 (M + H)+.
実施例317:
2−(ジメチルアミノ)エチル 4−オキソ−1−フェニル−3−(ピペリジン−4−イルメチル)−1,4−ジヒドロキノリン−2−カルボキシレート 塩酸塩
2−(ジメチルアミノ)エチル 4−オキソ−1−フェニル−3−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−1,4−ジヒドロキノリン−2−カルボキシレート
1H NMR (CDCl3): δ 8.45-8.43 (m, 1H), 7.80-7.78 (m, 2H), 7.56-7.54 (m, 4H), 7.45-7.40 (m, 5H), 7.34-7.31 (m, 1H), 6.78-6.76 (m, 1H), 6.47 (s, 1H), 3.94 (t, J = 6.1 Hz, 2H), 3.70 (s, 2H), 2.52-2.50 (m, 2H), 2.27 (t, J = 6.1 Hz, 2H), 2.17 (s, 6H), 2.13-2.08 (m, 2H), 1.92-1.83 (m, 1H), 1.76-1.65 (m, 4H), 1.41-1.35 (m, 2H);
マスデータ (APCI, Pos.): m/z 591 (M + H)+.
実施例319:
tert−ブチル 4−(3−(2−(2−(メチルアミノ)−2−オキソ−N−フェニルアセトアミド)フェニル)−3−オキソプロピル)ピペリジン−1−カルボキシレート
マスデータ (APCI, Pos.): m/z 494 (M + H)+.
実施例320:
tert−ブチル 4−((2−(メチルカルバモイル)−4−オキソ−1−フェニル−1,4−ジヒドロキノリン−3−イル)メチル)ピペリジン−1−カルボキシレート
マスデータ (APCI, Pos.): m/z 476 (M + H)+.
実施例321:
N−メチル−4−オキソ−1−フェニル−3−(ピペリジン−4−イルメチル)−1,4−ジヒドロキノリン−2−カルボキサアミド 塩酸塩
N−メチル−4−オキソ−1−フェニル−3−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−1,4−ジヒドロキノリン−2−カルボキサミド
1H NMR (CDCl3): δ 8.59-8.58 (m, 1H), 8.26-8.24 (m, 1H), 8.13-8.11 (m, 1H), 7.79-7.75 (m, 1H), 7.64 (s, 1H), 7.56-7.52 (m, 4H), 7.42-7.38 (m, 1H), 7.30-7.20 (m, 3H), 6.75-6.73 (m, 1H), 4.23-4.19 (m, 2H), 3.70 (s, 2H), 2.85-2.82 (m, 2H), 2.64 (d, J = 4.7 Hz, 3H), 2.05-1.96 (m, 2H), 1.59-1.53 (m, 2H), 1.32-1.22 (m, 2H), 0.94-0.88 (m, 2H);
マスデータ (APCI, Pos.): m/z 550 (M + H)+.
実施例323:
1−(2−(2,2−ジメトキシエチルアミノ)フェニル)−3−(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)プロパン−1−オン
マスデータ (APCI, Pos.): m/z 495 (M + H)+.
実施例324:
メチル 2−((2,2−ジメトキシエチル)(2−(3−(1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)プロパノイル)フェニル)アミノ)−2−オキソアセテート
マスデータ (APCI, Pos.): m/z 581 (M + H)+.
実施例325:
メチル 1−(2,2−ジメトキシエチル)−4−オキソ−3−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−1,4−ジヒドロキノリン−2−カルボキシレート
1H NMR (CDCl3): δ 8.60-8.59 (m, 1H), 8.44-8.42 (m, 1H), 8.14-8.12 (m, 1H), 7.79-7.75 (m, 1H), 7.66-7.62 (m, 3H), 7.39-7.35 (m, 1H), 7.31-7.27 (m, 1H), 4.61 (t, J = 5.0 Hz, 1H), 4.21 (s, 1H), 4.15-4.06 (m, 1H), 4.01 (s, 3H), 3.73 (s, 2H), 3.34 (s, 6H), 2.92-2.90 (m, 2H), 2.43 (d, J = 6.9 Hz, 2H), 2.04-2.02 (t, J = 5.0 Hz, 2H), 1.90-1.81 (m, 1H), 1.67-1.63 (m, 2H), 1.28-1.24 (m, 2H);
マスデータ (APCI, Pos.): m/z 563 (M + H)+.
実施例326:
tert−ブチル 4−(3−(2−(3−(ベンジルオキシカルボニルアミノ)プロピルアミノ)フェニル)−3−オキソプロピル)ピペリジン−1−カルボキシレート
マスデータ (APCI, Pos.): m/z 524 (M + H)+.
実施例327:
tert−ブチル 4−(3−(2−(N−(3−(ベンジルオキシカルボニルアミノ)プロピル)−2−メトキシ−2−オキソアセトアミド)フェニル)−3−オキソプロピル)ピペリジン−1−カルボキシレート
マスデータ (ESI, Pos.): m/z 632 (M+Na)+.
実施例328:
メチル 1−(3−(ベンジルオキシカルボニルアミノ)プロピル)−3−((1−(tert−ブトキシカルボニル)ピペリジン−4−イル)メチル)−4−オキソ−1,4−ジヒドロキノリン−2−カルボキシレート
マスデータ (APCI, Pos.): m/z 524 (M + H)+.
実施例329:
メチル 1−(3−(ベンジルオキシカルボニルアミノ)プロピル)−4−オキソ−3−(ピペリジン−4−イルメチル)−1,4−ジヒドロキノリン−2−カルボキシレート 塩酸塩
メチル 1−(3−(ベンジルオキシカルボニルアミノ)プロピル)−4−オキソ−3−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−1,4−ジヒドロキノリン−2−カルボキシレート
1H NMR (CDCl3): δ 8.60-8.59 (m, 1H), 8.46-8.43 (m, 1H), 8.14-8.13 (m, 1H), 7.79-7.75 (m, 1H), 7.66-7.62 (m, 2H), 7.42-7.35 (m, 6H), 7.31-7.27 (m, 2H), 5.12 (s, 2H), 4.96-4.92 (m, 2H), 4.05-4.02 (m, 2H), 3.93 (s, 3H), 3.72 (s, 2H), 3.31-3.27 (m, 2H), 2.91-2.88 (m, 2H), 2.36 (d, J = 6.9 Hz, 2H), 2.10-1.97 (m, 3H), 1.87-1.81 (m, 1H), 1.65-1.62 (m, 2H), 1.30-1.21 (m, 2H);
マスデータ (APCI, Pos.): m/z 666 (M + H)+.
実施例331:
メチル 1−(3−アミノプロピル)−4−オキソ−3−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−1,4−ジヒドロキノリン−2−カルボキシレート
1H NMR (CDCl3): δ 8.60-8.59 (m, 1H), 8.46-8.44 (m, 1H), 8.14-8.12 (m, 1H), 7.79-7.75 (m, 1H), 7.68-7.64 (m, 2H), 7.56-7.54 (m, 1H), 7.39-7.35 (m, 1H), 7.30-7.27 (m, 1H), 4.115-4.11 (m, 1H), 4.01 (s, 3H), 3.74 (s, 2H), 2.93-2.90 (m, 2H), 2.81 (t, J = 6.4 Hz, 2H), 2.39 (d, J = 6.9 Hz, 2H), 2.05-1.95 (m, 5H), 1.90-1.82 (m, 1H), 1.67-1.64 (m, 2H), 1.26-1.24 (m, 4H);
マスデータ (APCI, Pos.): m/z 532 (M + H)+.
実施例332:
メチル 4−オキソ−1−フェニル−3−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−1,4−ジヒドロ−2−キノリンカルボキシレート
1H NMR (CDCl3): δ 8.46-8.44 (m, 1H), 7.81-7.72 (m, 2H), 7.56-5.54 (m, 3H), 7.46-7.42 (m, 4H), 7.38-7.33 (m, 3H), 6.80-6.77 (m, 1H), 6.47 (s, 1H), 3.69 (s, 2H), 3.47 (s, 3H), 2.95-2.91 (m, 2H), 2.48 (d, J = 3.9 Hz, 2H), 2.13-2.07 (m, 2H), 1.94-1.86 (m, 1H), 1.76-1.71 (m, 2H), 1.39-1.29(m, 2H);
マスデータ (APCI, Pos.): m/z 534 (M+H)+ .
実施例333:
2−(チオフェン−2−イル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): d 10.02 (s, 1H), 8.33 (s, 1H), 7.69 (d, J = 3.9 Hz, 1H), 7.56 (d, J = 4.7 Hz, 1H), 7.15 (m, 1H);
マスデータ (ESI, Pos.): m/z 501 (M + H)+.
実施例334:
4−アミノ−5−シアノ−6−エトキシ−N−(ピペリジン−4−イルメチル)ピコリンアミド
マスデータ (APCI, Pos.): m/z 304 (M + H)+.
実施例335:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(チオフェン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.80 (br t, J = 6.3 Hz, 1H), 7.51 (s, 1H), 7.45 (d, J = 4.7 Hz, 1H), 7.37 (d, J = 6.3 Hz, 1H), 7.18 (s, 1H), 7.07 (m, 1H), 5.09 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.71 (s, 2H), 3.34 (t, J = 6.6 Hz, 2H), 2.98-2.93 (m, 2H), 2.07-2.00 (m, 2H), 1.76-1.70 (m, 2H), 1.62 (m, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.41-1.31 (m, 2H);
マスデータ (APCI, Pos.): m/z 483 (M + H)+.
実施例336:
4−アミノ−N−((1−((2−ブロモチアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 7.81 (br t, J = 6.3 Hz, 1H), 7.35 (s, 1H), 7.19 (s, 1H), 5.14 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.65 (s, 2H), 3.34 (t, J = 6.7 Hz, 2H), 2.93-2.89 (m, 2H), 2.05-1.98 (m, 2H), 1.75-1.69 (m, 2H), 1.61 (m, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.38-1.28 (m, 2H);
マスデータ (APCI, Pos.): m/z 479, 481(M + H)+.
実施例337:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(2−オキソピリジン−1(2H)−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.77 (m, 1H), 7.81 (br t, J = 6.3 Hz, 1H), 7.45 (s, 1H), 7.42 (m, 1H), 7.20 (s, 1H), 6.76 (d, J = 9.7 Hz, 1H), 6.41 (m, 1H), 5.14 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.75 (s, 2H), 3.33 (t, J = 6.6 Hz, 2H), 2.99-2.93 (m, 2H), 2.10-2.02 (m, 2H), 1.71 (m, 2H), 1.60 (m, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.42-1.32 (m, 2H);
マスデータ (APCI, Pos.): m/z 494 (M + H)+.
実施例338:
N−((1−((2−(1H−ピラゾール−3−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−4−アミノ−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 10.3 (br s, 1H), 7.80 (br t, J = 6.7 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.59 (s, 1H), 7.19 (s, 1H), 6.83 (d, J = 2.3 Hz, 1H), 5.11 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.75 (s, 2H), 3.34 (t, J = 6.7 Hz, 2H), 2.99-2.92 (m, 2H), 2.10-2.00 (m, 2H), 1.76-1.68 (m, 2H), 1.61 (m, 1H), 1.47-1.31 (m, 5H);
マスデータ (APCI, Pos.): m/z 467(M + H)+.
実施例339:
2−オキソ−1,2−ジヒドロピリジン−3−カルボチオアミド
1H NMR (DMSO-d6): δ 12.64 (br s, 1H), 11.33 (br s, 1H), 10.01 (br s, 1H), 8.95 (dd, J = 7.8, 2.3 Hz, 1H), 7.79 (m, 1H), 6.54 (t, J = 7.0 Hz, 1H);
マスデータ (APCI, Pos.): m/z 155(M + H)+.
実施例340:
2−(2−オキソ−1,2−ジヒドロピリジン−3−イル)チアゾール−5−カルバアルデヒド
1H NMR (DMSO-d6): δ 12.72 (br s, 1H), 10.09 (s, 1H), 8.75 (s, 1H), 8.66 (dd, J = 7.4, 2.0 Hz, 1H), 7.82 (dd, J = 5.8, 2.0 Hz, 1H), 6.54 (m, 1H);
マスデータ (APCI, Pos.): m/z 207(M + H)+.
実施例341:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(2−オキソ−1,2−ジヒドロピリジン−3−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 12.06 (br s, 1H), 8.52 (dd, J = 7.0, 2.3 Hz, 1H), 7.85 (br t, J = 6.7 Hz, 1H), 7.66 (s, 1H), 7.37 (m, 1H) 7.22 (s, 1H), 6.39 (t, J = 7.0 Hz, 1H) 6.18 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.79 (s, 2H), 3.31 (t, J = 6.3 Hz, 2H), 2.97-2.92 (m, 2H), 2.09-2.01 (m, 2H), 1.73-1.67 (m, 2H), 1.58 (m, 1H), 1.43 (t, J = 7.0 Hz, 3H), 1.40-1.29 (m, 2H);
マスデータ (ESI, Pos.): m/z 494 (M + H)+.
実施例342:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((1−フェニル−1H−イミダゾール−2−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.80 (m, 1H), 7.70 (d, J = 7.0 Hz, 2H), 7.57 (s, 1H), 7.46-7.41 (m, 2H), 7.40-7.34 (m, 2H), 7.19 (s, 1H), 5.14 (br s, 2H) 4.42 (q, J = 7.0 Hz, 2H), 3.46 (s, 2H), 3.33 (t, J = 6.3 Hz, 2H), 3.01-2.93 (m, 2H), 1.99-1.90 (m, 2H), 1.74-1.67 (m, 2H), 1.60 (m, 1H), 1.43 (t, J = 7.0 Hz, 3H), 1.40-1.28 (m, 2H);
マスデータ (APCI, Pos.): m/z460.1 (M + H)+.
実施例343:
4−アミノ−5−シアノ−6−エトキシ−N((1−((1−(ピリミジン−2−イル)−1H−イミダゾール−2−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.75 (d, J = 4.7 Hz, 2H), 7.91 (m, 1H), 7.86 (d, J = 1.6 Hz, 1H), 7.27 (t, J = 4.7 Hz, 1H), 7.07 (s, 1H), 7.01, (d, J = 1.6 Hz, 1H), 4.39, (q, J = 7.0 Hz, 2H), 4.15 (s, 2H), 3.24 (t, J = 6.3 Hz, 2H), 2.98-2.92 (m, 2H), 2.16-2.07 (m, 2H), 1.66-1.59 (m, 2H), 1.54 (m, 1H), 1.42 (t, J = 7.0 Hz, 3H), 1.18-1.06 (m, 2H);
マスデータ (APCI, Pos): m/z 462.2 (M + H)+.
実施例344:
2,6−ジフルオロベンゾチオアミド
1H NMR (CDCl3): δ 7.82 (s, 2H), 7.33 (m, 1H), 6.98-6.92 (m, 2H);
マスデータ (APCI, Neg): m/z 172.0 (M - H)-.
実施例345:
2−(2,6−ジフルオロフェニル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): δ 10.14 (s, 1H), 8.59 (s, 1H), 7.48 (m, 1H), 7.14-7.08 (m, 2H).
実施例346:
4−アミノ−5−シアノ−N−((1−((2−(2,6−ジフルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 7.84 (t, J = 6.3 Hz, 1H), 7.78 (s, 1H), 7.36 (m, 1H), 7.27 (s, 1H), 7.07-7.01 (m, 2H), 5.36 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.80 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 3.01-2.95 (m, 2H), 2.10-2.02 (m, 2H), 1.76-1.68 (m, 2H), 1.62 (m, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.42-1.32 (m, 2H);
マスデータ (APCI, pos) m/z 513.0 (M + H)+.
実施例347:
3−フルオロピリジン−2−カルボチオアミド
1H NMR (CDCl3): δ 8.99 (s, 2H), 8.39 (m, 1H), 7.63-7.45 (m, 2H);
マスデータ (APCI, pos) m/z 157.0 (M + H)+.
実施例348:
2−(3−フルオロピリジン−2−イル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): δ 10.12 (s, 1H), 8.58 (s, 1H), 8.54 (m, 1H), 7.64 (m, 1H), 7.49 (m, 1H).
実施例349:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(3−フルオロピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.47 (m, 1H), 7.82 (t, J = 6.3 Hz, 1H), 7.79 (s, 1H), 7.57 (m, 1H), 7.35 (m, 1H), 7.23 (s, 1H), 5.25 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.79 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 3.0-2.94 (m, 2H), 2.11-2.03 (m, 2H), 1.75-1.69 (m, 2H), 1.60 (m, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.42-1.32 (m, 2H);
マスデータ (APCI, pos) m/z 496.0 (M + H)+.
実施例350:
チアゾール−2−カルボニトリル
1H NMR (CDCl3): δ 9.05 (s, 1H), 8.43 (s, 1H).
実施例351:
チアゾール−2−カルボチオアミド
1H NMR (CDCl3): δ 8.87 (s, 1H), 8.22 (s, 1H);
マスデータ (APCI, pos) m/z 145.1 (M + H)+.
実施例352:
2,2’−ビチアゾール−5−カルバアルデヒド
1H NMR (CDCl3): δ 10.06 (s, 1H), 8.96 (s, 1H), 8.46 (s, 1H), 8.39 (s, 1H).
実施例353:
N−((1−(2,2’−ビチアゾール−5−イルメチル)ピペリジン−4−イル)メチル−4−アミノ−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 8.81 (s, 1H), 8.23 (s, 1H), 7.81 (t, J = 6.3 Hz, 1H), 7.57 (s, 1H), 7.20 (s, 1H), 5.14 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.73 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.98-2.93 (m, 2H), 2.09-2.01 (m, 2H), 1.77-1.70 (m, 2H), 1.63 (m, 1H), 1.44 (t, J = 7.0 Hz, 3H), 1.43-1.32 (m, 2H);
マスデータ (APCI, pos) m/z 483.9 (M + H)+.
実施例354:
3−クロロチオフェン−2−カルボチオアミド
1H NMR (CDCl3): δ 8.31 (s, 2H), 7.76 (s, 1H), 7.57 (d, J = 5.4 Hz, 1H), 7.06 (d, J = 5.4 Hz, 1H).
実施例355:
2−(3−クロロチオフェ−2−イル)チアゾール−5−カルバアルデヒド
1H NMR (CDCl3): δ 10.09 (s, 1H), 8.40 (s, 1H), 7.53 (d, J = 5.4 Hz, 1H), 7.10 (d, J = 5.4 Hz, 1H).
実施例356:
4−アミノ−N−((1−((2−(3−クロロチオフェ−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−5−シアノ−6−エトキシピコリンアミド
1H NMR (DMSO-d6): δ 8.45 (t, J = 6.3 Hz, 1H), 7.79 (d, J = 5.5 Hz, 1H), 7.72 (s, 1H), 7.29 (s, 2H), 7.23 (d, J = 5.5 Hz, 1H), 7.03 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.75 (s, 2H), 3.18-3.14 (m, 2H), 2.89-2.83 (m, 2H), 2.00-1.92 (m, 2H), 1.64-1.58 (m, 2H), 1.54 (m, 1H), 1.31 (t, J = 7.0 Hz, 3H), 1.26-1.14 (m, 2H);
マスデータ (APCI, pos) m/z 516.9 (M + H)+.
実施例357:
1−(2−(ピリジン−2−イル)チアゾール−5−イル)エタノール
1H NMR (CDCl3): δ 8.57 (d, J = 4.6 Hz, 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.76 (m, 1H), 7.68 (s, 1H), 7.29 (m, 1H), 5.19 (m, 1H), 3.29 (s, 1H), 1.62 (d, J = 6.4 Hz, 3H).
実施例358:
1−(2−(ピリジン−2−イル)チアゾール−5−イル)エタノン
1H NMR (CDCl3): δ 8.64 (d, J = 4.5 Hz, 1H), 8.39 (s, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.83 (m, 1H), 7.39 (m, 1H), 2.62 (s, 3H).
実施例359:
tert−ブチル (1−(1−(2−(ピリジン−2−イル)チアゾール−5−イル)エチル)ピペリジン−4−イル)メチル カルバメート
1H NMR (CDCl3): δ 8.60 (d, J = 4.7 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.78 (m, 1H), 7.63 (s, 1H), 7.30 (m, 1H), 4.57 (s, 1H), 4.02 (q, J = 7.0 Hz, 1H), 3.00 (t, J = 5.4 Hz, 2H), 2.93 (m, 1H), 2.86 (m, 1H), 2.18-2.07 (m, 2H), 1.70-1.63 (m, 2H), 1.47 (d, J = 7.0 Hz, 3H), 1.43 (s, 9H), 1.37 (m, 1H), 1.31-1.21 (m, 2H).
実施例360:
(1−(1−(2−(ピリジン−2−イル)チアゾール−5−イル)エチル)ピペリジン−4−イル)メタンアミン 三塩酸塩
1H NMR (10:1 CDCl3:MeOD-d3): δ 8.71 (d, J = 3.9 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 8.16 (s, 1H), 8.06 (m, 1H), 7.58 (m, 1H), 4.96 (m, 1H), 3.54-3.49 (m, 2H), 3.08-2.96 (m, 2H), 2.89-2.84 (m, 2H), 2.16 (m, 1H), 2.08-2.00 (m, 2H), 1.96 (d, J = 6.3 Hz, 3H);
マスデータ (APCI, pos) m/z 302.9 (M + H)+.
実施例361:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(1−(2−(ピリジン−2−イル)チアゾール−5−イル)エチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.60 (d, J = 4.7 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.82-7.76 (m, 2H), 7.62 (s, 1H), 7.30 (m, 1H), 7.22 (s, 1H), 5.22 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 4.30 (m, 1H), 3.32 (t, J = 6.3 Hz, 2H), 2.95 (m, 1H), 2.87 (m, 1H), 2.22-2.09 (m, 2H), 1.76-1.67 (m, 2H), 1.55 (m, 1H), 1.48 (d, J = 7.0 Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H), 1.40-1.30 (m, 2H);
マスデータ (ESI, pos) m/z 492.1 (M + H)+.
実施例362:
4−アミノ−N−((1−(ビフェニル−2−イルメチル)ピペリジン−4−イル)メチル)−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 7.80 (m, 1H), 7.53 (m, 1H), 7.40-7.36 (m, 4H), 7.35 (m, 1H), 7.34-7.29 (m, 2H), 7.25-7.22 (m, 2H), 5.28 (br s, 2H), 4.42 (q, J = 7.0 Hz, 2H), 3.38 (s, 2H), 3.30 (t, J = 6.3 Hz, 2H), 2.84-2.78 (m, 2H), 1.89-1.81 (m, 2H), 1.66-1.61 (m, 2H), 1.52 (m, 1H), 1.43 (t, J = 7.0 Hz, 3H), 1.34-1.24 (m, 2H);
マスデータ (APCI, pos) m/z 470.2 (M + H)+.
実施例363:
tert−ブチル (1−(1−(ビフェニル−4−イル)−1−シアノエチル)ピペリジン−4−イル)メチルカーバメート
1H NMR (CDCl3): δ 7.66-7.62 (m, 2H), 7.61-7.57 (m, 4H), 7.48-7.42 (m, 2H), 7.36 (m, 1H), 4.56 (br s, 1H), 3.27 (m, 1H), 3.04 (br t, J = 6.3 Hz, 2H), 2.62 (m, 1H), 2.29 (dt, J = 11.0, 3.1 Hz, 1H), 2.08 (br dt, J = 11.0, 2.3 Hz, 1H), 1.85 (m, 1H), 1.74 (s, 3H), 1.63-1.32 (m, 12 H), 1.17 (dq, J = 12.0, 3.9 Hz, 1H);
マスデータ (APCI, Pos.): m/z 420(M + H)+.
実施例364:
tert−ブチル (1−(2−(ビフェニル−4−イル)プロピル−2−イル)ピペリジン−4−イル)メチルカーバメート
1H NMR (CDCl3): δ 7.61-7.57 (m, 4H), 7.54-7.51 (m, 2H), 7.45-7.40 (m, 2H), 7.32 (m, 1H), 4.56 (br s, 1H), 3.03-2.99 (m, 2H), 2.88-2.83 (m, 2H), 2.11-2.05 (m, 2H), 1.66-1.61 (m, 2H), 1.45-1.38 (m, 10 H), 1.36 (s, 6H), 1.26-1.16 (m, 2H);
マスデータ (ESI, Pos.): m/z 409 (M + H)+.
実施例365:
4−アミノ−N−((1−(2−(ビフェニル−4−イル)プロパン−2−イル)ピペリジン−4−イル)メチル)−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 7.80 (br t, J = 5.9 Hz, 1H), 7.61-7.56 (m, 4H), 7.53-7.51 (m, 2H), 7.45-7.41 (m, 2H), 7.32 (m, 1H), 7.18 (s, 1H), 5.07 (br s, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.33 (t, J = 6.7 Hz, 2H), 2.91-2.85 (m, 2H), 2.14-2.07 (m, 2H), 1.71-1.66 (m, 2H), 1.57 (m, 1H), 1.44 (t, J = 7.0 Hz, 3 H), 1.37-1.25 (m, 8H);
マスデータ (ESI, Pos.): m/z 498 (M + H)+.
実施例366:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(4−(ピリジン−2−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.68 (d, J = 4.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.80-7.79 (m, 1H), 7.75-7.71 (m, 2H), 7.41 (d, J = 8.2 Hz, 2H), 7.23-7.21 (m, 1H), 7.19 (s, 1H), 5.10 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.55 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.94-2.91 (m, 2H), 2.01-1.96 (m, 2H), 1.69-1.56 (m, 4H), 1.44 (t, J = 7.1 Hz, 3H), 1.42-1.39 (m, 2H);
マスデータ (ESI, Pos.): m/z 471 (M + H)+.
実施例367:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(4−(ピラジン−2−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 9.02 (d, J = 1.5 Hz, 1H), 8.65-8.60 (m, 1H), 8.50 (d, J = 2.5 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.86-7.77 (m, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.19 (s, 1H), 5.11 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.97-2.88 (m, 2H), 2.06-1.94 (m, 2H), 1.76-1.67 (m, 2H), 1.66-1.54 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.40-1.31 (m, 1H);
マスデータ (ESI, Pos.): m/z 472 (M + H)+.
実施例368:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(4−(ピリミジン−5−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 9.20 (s, 1H), 8.95 (s, 2H), 7.85-7.76 (m, 1H), 7.55-7.50 (m, 2H), 7.49-7.45 (m, 2H), 7.19 (s, 1H), 5.11 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 3.35 (t, J = 6.5 Hz, 2H), 2.97-2.87 (m, 2H), 2.02-2.00 (m, 2H), 1.77-1.67 (m, 2H), 1.68-1.58 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.41-1.35 (m, 2H);
マスデータ (ESI, Pos.): m/z 472 (M + H)+.
実施例369:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(3−(ピラジン−2−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 9.03 (d, J = 1.5 Hz, 1H), 8.65-8.62 (m, 1H), 8.51 (d, J= 2.5 Hz, 1H), 7.96 (s, 1H), 7.90-7.87 (m, 1H), 7.83-7.77 (m, 1H), 7.47-7.43 (m, 2H), 7.19 (s, 1H), 5.12 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.59 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.97-2.90 (m, 2H), 2.05-1.97 (m, 2H), 1.75-1.67 (m, 2H), 1.65-1.58 (m, 1H), 1.43 (t, J= 7.1 Hz, 3H), 1.40-1.34 (m, 2H);
マスデータ (ESI, Pos.): m/z 472 (M + H)+.
実施例370:
4−アミノ−N−((1−(ビフェニル−4−イルメチル)ピペリジン−4−イル)メチル)−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 7.85-7.78 (m, 1H), 7.59 (d, J = 7.3 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.39-7.31 (m, 3H), 7.21 (s, 1H), 5.17 (s, 2H), 4.43 (q, J= 7.1 Hz, 2H), 3.53 (s, 2H), 3.34 (t, J= 6.5 Hz, 2H), 2.98-2.91 (m, 2H), 2.04-1.95 (m, 2H), 1.75-1.68 (m, 2H), 1.66-1.60 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.40-1.35 (m, 2H);
マスデータ (ESI, Pos.): m/z 470 (M + H)+.
実施例371:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(4−(ピリジン−4−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.65 (d, J = 6.1 Hz, 2H), 7.83-7.78 (m, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 6.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.19 (s, 1H), 5.13 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.55 (s, 2H), 3.35 (t, J = 6.5 Hz, 2H), 2.95-2.89 (m, 2H), 2.04-1.96 (m, 2H), 1.76-1.68 (m, 2H), 1.66-1.59 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.40-1.34 (m, 2H);
マスデータ (ESI, Pos.): m/z 471 (M + H)+.
実施例372:
4−アミノ−N−((1−(ビフェニル−3−イルメチル)ピペリジン−4−イル)メチル)−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 7.84-7.76 (m, 1H), 7.62-7.57 (m, 2H), 7.53 (s, 1H), 7.50-7.27 (m, 6H), 7.20 (s, 1H), 5.14 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.98-2.90 (m, 2H), 2.04-1.94 (m, 2H), 1.74-1.67 (m, 2H), 1.65-1.59 (m, 1H), 1.43 (t, J = 7.1 Hz, 3H), 1.39-1.33 (m, 2H);
マスデータ (ESI, Pos.): m/z 470 (M + H)+.
実施例373:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(3−(ピリジン−2−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.69 (d, J = 4.9 Hz, 1H), 7.92 (s, 1H), 7.86 (d, J = 7.4 Hz, 1H), 7.83-7.70 (m, 3H), 7.45-7.35 (m, 2H), 7.24-7.20 (m, 1H), 7.18 (s, 1H), 5.10 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.58 (s, 2H), 3.33 (t, J = 6.5 Hz, 2H), 2.99-2.89 (m, 2H), 2.05-1.94 (m, 2H), 1.74-1.66 (m, 2H), 1.65-1.59 (m, 1H), 1.43 (t, J= 7.1 Hz, 3H), 1.39-1.33 (m, 2H);
マスデータ (ESI, Pos.): m/z 471 (M + H)+.
実施例374:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(3−(ピリジン−3−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.85 (d, J= 1.7 Hz, 1H), 8.60-8.57 (m, 1H), 7.90-7.86 (m, 1H), 7.84-7.79 (m, 1H), 7.54 (s, 1H), 7.49-7.39 (m, 2H), 7.38-7.33 (m, 2H), 7.22 (s, 1H), 5.22 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.57 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.97-2.90 (m, 2H), 2.05-1.96 (m, 2H), 1.75-1.68 (m, 2H), 1.66-1.57 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.40-1.34 (m, 1H);
マスデータ (ESI, Pos.): m/z 471 (M + H)+.
実施例375:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(3−(ピリジン−4−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.66 (d, J = 6.1 Hz, 2H), 7.85-7.78 (m, 1H), 7.59 (s, 1H), 7.55-7.49 (m, 3H), 7.46-7.36 (m, 2H), 7.21 (s, 1H), 5.17 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.57 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.96-2.89 (m, 2H), 2.04-1.96 (m, 2H), 1.76-1.67 (m, 2H), 1.67-1.56 (m, 1H), 1.43 (t, J = 7.1 Hz, 3H), 1.40-1.33 (m, 2H);
マスデータ (ESI, Pos.): m/z 471 (M + H)+.
実施例376:
N−((1−(4−(1H−ピラゾール−1−イル)ベンジル)ピペリジン−4−イル)メチル)−4−アミノ−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 7.91 (d, J = 2.4 Hz, 1H), 7.85-7.80 (m, 1H), 7.72 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.25 (s, 1H), 6.46 (t, J = 2.1 Hz, 1H), 5.26 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.52 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.94-2.88 (m, 2H), 2.03-1.94 (m, 2H), 1.75-1.67 (m, 2H), 1.66-1.55 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.39-1.32 (m, 2H);
マスデータ (ESI, Pos.): m/z 460 (M + H)+.
実施例377:
N−((1−(4−(1H−1,2,4−トリアゾール−1−イル)ベンジル)ピペリジン−4−イル)メチル)−4−アミノ−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 8.53 (s, 1H), 8.10 (s, 1H), 7.85-7.78 (m, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.21 (s, 1H), 5.17 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.54 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.93-2.85 (m, 2H), 2.03-1.95 (m, 2H), 1.76-1.68 (m, 2H), 1.67-1.59 (m, 1H), 1.44 (t, J= 7.1 Hz, 3H), 1.39-1.33 (m, 2H);
マスデータ (ESI, Pos.): m/z 461 (M + H)+.
実施例378:
N−((1−(4−(1H−イミダゾール−1−イル)ベンジル)ピペリジン−4−イル)メチル)−4−アミノ−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 7.84 (s, 1H), 7.83-7.79 (m, 1H), 7.45-7.40 (m, 2H), 7.35-7.31 (m, 2H), 7.28-7.26 (m, 1H), 7.22-7.19 (m, 2H), 5.19 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.54 (s, 2H), 3.35 (t, J= 6.5 Hz, 2H), 2.95-2.87 (m, 2H), 2.04-1.96 (m, 2H), 1.77-1.69 (m, 2H), 1.68-1.58 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.41-1.34 (m, 2H);
マスデータ (ESI, Pos.): m/z 460 (M + H)+.
実施例379:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(4−モルホリノベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.82-7.76 (m, 1H), 7.22-7.17 (m, 3H), 6.86 (d, J = 8.6 Hz, 2H), 5.09 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.88-3.82 (m, 4H), 3.42 (s, 2H), 3.32 (t, J = 6.5 Hz, 2H), 3.17-3.11 (m, 4H), 2.93-2.85 (m, 2H), 1.97-1.88 (m, 2H), 1.73-1.64 (m, 2H), 1.57 (s, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.35 (s, 2H);
マスデータ (ESI, Pos.): m/z 479 (M + H)+.
実施例380:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(4−(4−メチルピペラジン−1−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.80 (d, J = 6.2 Hz, 1H), 7.25 (s, 1H), 7.18 (d, J = 8.5 Hz, 2H), 6.87 (d, J= 8.6 Hz, 2H), 5.30 (s, 2H), 4.42 (q, J= 7.1 Hz, 2H), 3.41 (s, 2H), 3.32 (t, J= 6.5 Hz, 2H), 3.23-3.16 (m, 4H), 2.94-2.86 (m, 2H), 2.61-2.53 (m, 4H), 2.35 (s, 3H), 1.98-1.88 (m, 2H), 1.72-1.65 (m, 2H), 1.63-1.52 (m, 1H), 1.43 (t, J = 7.1 Hz, 3H), 1.39-1.29 (m, 2H);
マスデータ (ESI, Pos.): m/z 492 (M + H)+.
実施例381:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((2’−メチルビフェニル−4−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.85-7.78 (m, 1H), 7.36-7.31 (m, 2H), 7.29-7.21 (m, 6H), 7.20 (s, 1H), 5.12 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.54 (s, 2H), 3.35 (t, J = 6.5 Hz, 2H), 2.99-2.92 (m, 2H), 2.27 (s, 3H), 2.05-1.95 (m, 2H), 1.76-1.68 (m, 2H), 1.67-1.57 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.41-1.33 (m, 2H);
マスデータ (ESI, Pos.): m/z 484 (M + H)+.
実施例382:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((4’−メチルビフェニル−4−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.84-7.77 (m, 1H), 7.54-7.45 (m, 4H), 7.35 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.18 (s, 1H), 5.08 (s, 2H), 4.43 (q, J= 7.1 Hz, 2H), 3.52 (s, 2H), 3.34 (t, J= 6.5 Hz, 2H), 2.98-2.89 (m, 2H), 2.39 (s, 3H), 2.04-1.94 (m, 2H), 1.75-1.67 (m, 2H), 1.66-1.57 (m, 1H), 1.44 (t, J= 7.1 Hz, 3H), 1.40-1.32 (m, 2H);
マスデータ (ESI, Pos.): m/z 484 (M + H)+.
実施例383:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(4−(ピリミジン−2−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.80 (d, J = 4.8 Hz, 2H), 8.38 (d, J= 7.9 Hz, 2H), 7.85-7.76 (m, 1H), 7.48-7.40 (m, 2H), 7.18 (s, 2H), 5.08 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.57 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.97-2.86 (m, 2H), 2.03-1.93 (m, 2H), 1.76-1.67 (m, 2H), 1.66-1.57 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.40-1.30 (m, 2H);
マスデータ (ESI, Pos.): m/z 472 (M + H)+.
実施例384:
4−アミノ−5−シアノ−6−エトキシ−N−((1−(4−(2−メチルチアゾール−4−イル)ベンジル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.81 (d, J = 8.1 Hz, 2H), 7.34 (d, J= 8.1 Hz, 2H), 7.28 (s, 1H), 7.19 (s, 1H), 5.11 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.52 (s, 2H), 3.49 (s, 1H), 3.33 (t, J = 6.5 Hz, 2H), 2.95-2.87 (m, 2H), 2.77 (s, 3H), 2.01-1.93 (m, 2H), 1.74-1.66 (m, 2H), 1.65-1.58 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.39-1.33 (m, 2H);
マスデータ (ESI, Pos.): m/z 491 (M + H)+.
実施例385:
4−アミノ−5−シアノ−6−エトキシ−N−((1−((3’−メチルビフェニル−4−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.85-7.77 (m, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.41-7.29 (m, 5H), 7.19 (s, 1H), 7.15 (d, J = 7.4 Hz, 1H), 5.11 (s, 2H), 4.43 (q, J= 7.1 Hz, 2H), 3.53 (s, 2H), 3.34 (t, J= 6.4 Hz, 2H), 2.98-2.90 (m, 2H), 2.42 (s, 3H), 2.05-1.93 (m, 2H), 1.76-1.67 (m, 2H), 1.67-1.58 (m, 1H), 1.44 (t, J= 7.1 Hz, 3H), 1.41-1.32 (m, 2H);
マスデータ (ESI, Pos.): m/z 484 (M + H)+.
実施例386:
メチル 3’−((ジメチルアミノ)メチル)ビフェニル−4−カルボキシレート
1H NMR (CDCl3): δ 8.13-8.07 (m, 2H), 7.70-7.63 (m, 2H), 7.60-7.39 (m, 3H), 7.36-7.32 (m, 1H), 3.94 (s, 3H), 3.50 (s, 2H), 2.28 (s, 6H).
実施例387:
(3’−((ジメチルアミノ)メチル)ビフェニル−4−イル)メタノール
マスデータ (ESI, Pos.): m/z 242 (M + H)+.
実施例388:
3’−((ジメチルアミノ)メチル)ビフェニル−4−カルバアルデヒド
マスデータ (ESI, Pos.): m/z 240 (M + H)+.
実施例389:
4−アミノ−5−シアノ−N−((1−((3’−((ジメチルアミノ)メチル)ビフェニル−4−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 7.84-7.77 (m, 1H), 7.57-7.46 (m, 3H), 7.41-7.33 (m, 3H), 7.30-7.26 (m, 2H), 7.18 (s, 1H), 5.09 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.53 (s, 2H), 3.49 (s, 2H), 3.37-3.31 (m, 2H), 2.97-2.89 (m, 2H), 2.27 (s, 6H), 2.03-1.94 (m, 2H), 1.77-1.67 (m, 2H), 1.66-1.56 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.40-1.33 (m, 2H);
マスデータ (ESI, Pos.): m/z 527 (M + H)+.
実施例390:
N−((1−(2,2’−ビピリジン−5−イルメチル)ピペリジン−4−イル)メチル)−4−アミノ−5−シアノ−6−エトキシピコリンアミド
1H NMR (CDCl3): δ 8.68 (d, J = 4.6 Hz, 1H), 8.59 (s, 1H), 8.41-8.32 (m, 2H), 7.84-7.76 (m, 3H), 7.34-7.27 (m, 1H), 7.19 (s, 1H), 5.13 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 3.57 (s, 2H), 3.34 (t, J = 6.5 Hz, 2H), 2.95-2.86 (m, 2H), 2.07-1.97 (m, 2H), 1.76-1.68 (m, 2H), 1.67-1.59 (m, 1H), 1.44 (t, J = 7.1 Hz, 3H), 1.40-1.32 (m, 2H);
マスデータ (ESI, Pos.): m/z 472 (M + H)+.
実施例391:
tert−ブチル (1−((2−(2−フルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチルカルバメート
1H NMR (CDCl3): δ 8.27-8.21 (m, 1H), 7.69 (s, 1H), 7.41-7.34 (m, 1H), 7.25-7.16 (m, 2H), 4.59 (bs, 1H), 3.78 (s, 2H), 3.06-3.00 (m, 2H), 2.95 (d, J = 10.2 Hz, 2H), 2.03 (t, J = 11.7 Hz, 2H), 1.68 (d, J = 11.7 Hz, 2H), 1.51-1.40 (m, 10H), 1.34-1.24 (m, 2H);
マスデータ (ESI, Pos.): m/z 428 (M + Na)+.
実施例392:
(1−((2−(2−フルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メタンアミン 三塩酸塩
1H NMR (DMSO-d6): δ 11.45 (s, 1H), 8.30-8.14 (m, 4H), 7.63-7.56 (m, 1H), 7.50-7.39 (m, 2H), 6.85 (bs, 2H), 4.65 (d, J = 4.7 Hz, 2H), 3.44 (d, J= 11.7 Hz, 2H), 3.00-2.89 (m, 2H), 2.74-2.67 (m, 2H), 2.01-1.83 (m, 3H), 1.64-1.51 (m, 2H);
マスデータ (ESI, Pos.): m/z 306 (M + H)+.
実施例393:
4−アミノ−6−クロロ−5−シアノ−N−((1−((2−(2−フルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): d 8.57 (t, J = 5.9 Hz, 1H), 8.20 (t, J = 7.8 Hz, 1H), 7.82 (s, 1H), 7.81-7.67 (bs, 1H), 7.56-7.49 (m, 1H), 7.45-7.34 (m, 4H), 3.76 (s, 2H), 3.15 (t, J = 6.3 Hz, 2H), 2.86 (d, J = 11.0 Hz, 2H), 1.96 (t, J = 11.0 Hz, 2H), 1.65-1.53 (m, 3H), 1.24-1.10 (m, 2H);
マスデータ (APCI, Pos.): m/z 485 (M + H)+.
実施例394:
4−アミノ−5−シアノ−6−(シクロプロピルメトキシ)−N−((1−((2−(2−フルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.27-8.20 (m, 1H), 7.82-7.75 (m, 1H), 7.69 (s, 1H), 7.42-7.35 (m, 1H), 7.25-7.16 (m, 3H), 5.16 (s, 2H), 4.21 (d, J = 7.0 Hz, 2H), 3.78 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.97 (d, J = 11 Hz, 2H), 2.10-2.01 (m, 2H), 1.73 (d, J = 12.5 Hz, 2H), 1.67-1.57 (m, 1H), 1.43-1.24 (m, 3H), 0.66-0.60 (m, 2H), 0.40-0.35 (m, 2H);
マスデータ (ESI, Pos.): m/z 543 (M + Na)+.
実施例395:
4−アミノ−5−シアノ−N−((1−((2−(2−フルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−イソプロポキシピコリンアミド
1H NMR (CDCl3): δ 8.26-8.20 (m, 1H), 7.85-7.78 (m, 1H), 7.69 (s, 1H), 7.41-7.35 (m, 1H), 7.27-7.15 (m, 3H), 5.37 (s, 2H), 5.32-5.24 (m, 1H), 3.78 (s, 2H), 3.34 (t, J = 6.7 Hz, 2H), 2.97 (d, J = 11.0 Hz, 2H), 2.11-2.01 (m, 2H), 1.72 (d, J= 12.5 Hz, 2H), 1.66-1.55 (m, 1H), 1.45-1.33 (m, 8H);
マスデータ (ESI, Pos.): m/z 531 (M + Na)+.
実施例396:
4−アミノ−5−シアノ−6−(ネオペンチルオキシ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.60 (d, J = 4.7 Hz, 1H), 8.14 (d, J= 7.8 Hz, 1H), 7.84-7.76 (m, 2H), 7.67 (s, 1H), 7.32-7.28 (m, 1H), 7.25 (m, 1H), 5.29 (s, 2H), 4.00 (s, 2H), 3.78 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.97 (d, J= 11.0 Hz, 2H), 2.12-2.05 (m, 2H), 1.72 (d, J = 12.5 Hz, 2H), 1.67-1.56 (m, 1H), 1.43-1.32 (m, 2H), 1.06 (s, 9H);
マスデータ (ESI, Pos.): m/z 542 (M + Na)+.
実施例397:
tert−ブチル (1−((2−(2,6−ジフルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチルカルバメート
1H NMR (CDCl3): δ 7.78 (2, 1H), 7.38-7.33 (m, 1H), 7.06-7.02 (m, 2H), 4.59 (bs, 1H), 3.79 (s, 2H), 3.04-2.94 (m, 4H), 2.04 (t, J = 11.7 Hz, 2H), 1.68 (d, J = 11.7 Hz, 2H), 1.51-1.40 (m, 10H), 1.31-1.25 (m, 2H);
マスデータ (ESI, Pos.): m/z 446 (M + Na)+.
実施例398:
(1−((2−(2,6−ジフルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メタンアミン 二塩酸塩
4−アミノ−6−クロロ−5−シアノ−N−((1−((2−(2,6−ジフルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.88-7.85 (m, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.40-7.32 (m, 1H), 7.04 (t, J = 8.6 Hz, 2H), 5.50 (bs, 2H), 3.80 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.98 (bd, J = 10.2 Hz, 2H), 2.06 (t, J = 11.0 Hz, 2H), 1.75 (bd, J = 12.5 Hz, 2H), 1.68-1.52 (m, 1H), 1.42-1.33 (m, 2H);
マスデータ (APCI, Pos.): m/z 503 (M + H)+.
実施例400:
4−アミノ−5−シアノ−N−((1−((2−(2,6−ジフルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−イソプロポキシピコリンアミド
1H NMR (CDCl3): δ 7.78 (bs, 2H), 7.40-7.33 (m, 1H), 7.17 (s, 1H), 7.04 (t, J = 8.6 Hz, 2H), 5.32-5.26 (m, 1H), 5.09 (bs, 2H), 3.80 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.98 (bd, J = 11.0 Hz, 2H), 2.07 (t, J = 11.0 Hz, 2H), 1.73 (bd, J = 11.7 Hz, 2H), 1.65-1.55 (m, 1H), 1.42-1.37 (m, 8H);
マスデータ (APCI, Pos.): m/z 527 (M + H)+.
実施例401:
4−アミノ−5−シアノ−6−(シクロプロピルメトキシ)−N−((1−((2−(2,6−ジフルオロフェニル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 7.78 (bs, 2H), 7.40-7.32 (m, 1H), 7.20 (s, 1H), 7.04 (t, J = 8.6 Hz, 2H), 5.16 (bs, 2H), 4.21 (d, J = 7.0 Hz, 2H), 3.80 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.97 (bd, J = 11.7 Hz, 2H), 2.06 (t, J = 11.0 Hz, 2H), 1.72 (bd, J = 11.7 Hz, 2H), 1.66-1.57 (m, 1H), 1.42-1.35 (m, 2H), 1.33-1.28 (m, 1H), 0.66-0.61 (m, 2H), 0.40-0.36 (m, 2H);
マスデータ (APCI, Pos.): m/z 539 (M + H)+.
実施例402:
4−アミノ−6−クロロピリジン−2(1H)−オン
1H NMR(DMSO-d6): δ 10.53 (br s, 1H), 6.18 (s, 2H), 6.05 (s, 1H), 5.59 (s, 1H);
マスデータ (APCI, Pos.): m/z 145 (M + H)+.
実施例403:
4−アミノ−6−クロロピリジン−2−イル トリフルオロメタンスルホネート
1H NMR(CDCl3): δ 7.26 (s, 1H), 6.58 (d, J = 1.6 Hz, 1H), 6.28 (d, J = 1.6 Hz, 1H), 4.61 (br, s, 2H);
マスデータ (APCI, Neg.): m/z 275 (M - H)-.
実施例404:
メチル 4−アミノ−6−クロロピコリネート
1H NMR(DMSO-d6): δ 7.21 (s, 1H), 6.75 (s, 2H), 6.65 (s, 1H), 3.82 (s, 3H);
マスデータ (APCI, Pos.): m/z 187 (M + H)+.
実施例405:
メチル 4−アミノ−5,6−ジクロロピコリネート
1H NMR(DMSO-d6): δ 7.41 (s, 1H), 7.09 (br s, 2H), 3.83 (s, 3H);
マスデータ (APCI, Pos.): m/z 221 (M + H)+.
実施例406:
4−アミノ−5,6−ジクロロピコリン酸
1H NMR(DMSO-d6): δ 13.22 (br, s, 1H), 7.39 (s, 1H), 7.03 (br s, 2H);
マスデータ (APCI, Neg.): m/z 205 (M - H)-.
実施例407:
4−アミノ−5,6−ジクロロ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR(CDCl3): δ 8.60 (d, J = 4.8 Hz, 1H), 8.14 (d, J = 8.0, 1H) 7.87-7.75 (m, 2H), 7.68 (s, 1H), 7.48 (s, 1H), 7.33-7.28 (m, 1H), 4.97 (s, 2H), 3.78 (s, 2H), 3.32 (t, J = 6.6 Hz, 2H), 3.01-2.93 (m, 2H), 2.13-2.01 (m, 2H), 1.79-1.68 (m, 2H), 1.67-1.62 (m, 1H), 1.44-1.30 (m, 2H);
マスデータ (APCI, Pos.): m/z 447 (M + H)+.
実施例408:
4−アミノ−5−クロロ−6−(2−ヒドロキシエチルアミン)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR(CDCl3): δ 8.58 (d, J = 4.3 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.93 (t, J = 6.0 Hz, 1H), 7.80-7.76 (M, 1H), 7.67 (s, 1H), 7.31-7.28 (m, 1H), 7.02 (s, 1H), 5.30 (t, J = 5.6 Hz, 1H), 4.69 (s, 2H), 3.87 (t, J = 5.3 Hz, 2H), 3.76 (s, 2H), 3.65 (q, J = 5.5, 2H), 3.32 (t, J = 6.1 Hz, 2H), 3.00-2.89 (m, 2H), 2.12-2.01 (m, 2H), 1.75-1.65 (m, 2H), 1.64-1.53 (m, 1H), 1.46-1.32 (m, 2H);
マスデータ (APCI, Pos.): m/z 502 (M + H)+.
実施例409:
4−アミノ−6−(3−アミノプロピルアミノ)−5−クロロ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR(CDCl3): δ 8.59 (d, J = 4.5 Hz, 1H), 8.18-8.02 (m, 2H), 7.81-7.74 (m, 1H), 7.67 (s, 1H), 7.33-7.27 (m, 1H), 6.98 (s, 1H), 5.47-5.34 (m, 1H), 4.61 (s, 1H), 4.55 (s, 1H), 3.76 (d, J = 3.3 Hz, 2H), 3.61-3.45 (m, 3H), 3.30 (d, J = 4.5 Hz, 2H), 3.00-2.84 (m, 2H), 2.46 (s, 2H), 2.11-2.00 (m, 2H), 1.98-1.90 (m, 2H), 1.86-1.78 (m, 1H), 1.77-1.65 (m, 2H), 1.65-1.50 (m, 1H), 1.43-1.29 (m, 2H);
マスデータ (APCI, Pos.): m/z 515 (M + H)+.
実施例410:
(R)−4−アミノ−5−クロロ−6−(1−ヒドロキシプロパン−2−イルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CD3OD): δ 8.57 (d, J = 4.7 Hz, 1H), 8.12 (d, J= 7.9 Hz, 1H), 7.93-7.87 (m, 1H), 7.75 (s, 1H), 7.46-7.39 (m, 1H), 6.86 (s, 1H), 4.33-4.22 (m, 1H), 3.84 (s, 2H), 3.68-3.60 (m, 1H), 3.58-3.51 (m, 1H), 3.40 (d, J = 5.6 Hz, 1H), 3.30-3.26 (m, 2H), 3.04-2.97 (m, 2H), 2.19-2.09 (m, 2H), 1.80-1.71 (m, 2H), 1.70-1.59 (m, 1H), 1.44-1.31 (m, 2H), 1.25 (d, J = 6.7 Hz, 2H);
マスデータ (ESI, Pos.): m/z 516 (M + H)+.
実施例411:
(R)−4−アミノ−5−クロロ−6−(2,3−ジヒドロキシプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CD3OD): δ 8.58 (d, J = 4.7 Hz, 1H), 8.14 (d, J= 7.9 Hz, 1H), 7.96-7.87 (m, 1H), 7.81 (s, 1H), 7.47-7.40 (m, 1H), 6.85 (s, 1H), 4.01 (s, 2H), 3.87-3.69 (m, 2H), 3.54 (d, J = 5.4 Hz, 2H), 3.47-3.38 (m, 1H), 3.29-3.24 (m, 2H), 3.18-3.07 (m, 2H), 2.42-2.25 (m, 2H), 1.87-1.77 (m, 2H), 1.77-1.65 (m, 1H), 1.49-1.33 (m, 2H);
マスデータ (ESI, Pos.): m/z 532 (M + H)+.
実施例412:
(S)−4−アミノ−5−クロロ−6−(2,3−ジヒドロキシプロピルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CD3OD): δ 8.57 (d, J = 4.7 Hz, 1H), 8.13 (d, J= 7.9 Hz, 1H), 7.95-7.87 (m, 1H), 7.80 (s, 1H), 7.46-7.39 (m, 1H), 6.85 (s, 1H), 3.98 (s, 2H), 3.86-3.70 (m, 2H), 3.55 (d, J = 5.3 Hz, 2H), 3.46-3.38 (m, 1H), 3.30-3.26 (m, 2H), 3.14-3.05 (m, 2H), 2.37-2.22 (m, 2H), 1.86-1.76 (m, 2H), 1.76-1.62 (m, 1H), 1.47-1.33 (m, 2H);
マスデータ (ESI, Pos.): m/z 532 (M + H)+.
実施例413:
4−アミノ−5−シアノ−6−(2−(6−フルオロ−1H−インドール−3−イル)エチルアミノ)−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR(DMSO-d6): δ 10.88 (s, 1H), 8.64-8.58 (m, 1H), 8.23-8.16 (m, 1H), 8.11-8.06 (m, 1H), 7.98-7.90 (m, 1H), 7.77 (s, 1H), 7.55-7.43 (m, 2H), 7.16 (s, 1H), 7.11-7.05 (m, 1H), 6.90 (s, 2H), 6.84-6.76 (m, 1H), 6.75-6.69 (m, 1H), 6.66 (s, 1H), 5.76 (s, 1H), 3.70 (s, 3H), 3.18-3.08 (m, 2H), 2.97-2.90 (m, 2H), 2.82-2.74 (m, 2H), 1.94-1.83 (m, 2H), 1.61-1.50 (m, 2H), 1.49-1.35 (m, 1H), 1.21-1.07 (m, 2H);
マスデータ (APCI, Pos.): m/z 610 (M + H)+.
実施例414:
4−アミノ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.60 (d, J = 3.9 Hz, 1H), 8.15-8.12 (m, 3H), 7.78 (dt, J = 7.8, 2.3, 1H), 7.67 (s, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.31-7.28 (m, 1H), 6.59 (dd, J = 5.5, 2.3 Hz, 1H), 5.30 (bs, 2H), 3.77 (s, 2H), 3.34 (t, J = 6.3 Hz, 2H), 2.96 (bd, J = 11.0 Hz, 2H), 2.06 (dt, J = 11.7, 2.3 Hz, 2H), 1.76 (bd, J = 12.5 Hz, 2H), 1.65-1.62 (m, 1H), 1.43-1.36 (m, 2H);
マスデータ (APCI, Pos.): m/z 409 (M + H)+.
実施例415:
tert−ブチル 4−カルバモイル−4−メチルピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 3.49-3.59 (m, 2H), 2.98-3.06 (br, 2H), 1.86-1.92 (m, 2H), 1.38 (s, 9H), 1.18-1.25 (m, 4H), 1.06 (s, 3H);
マスデータ (APCI, Pos.): m/z 143 (M + H - Boc)+.
実施例416:
tert−ブチル 4−(アミノメチル)−4−メチルピペリジン−1−カルボキシレート
残渣をメタノール(5 mL)で希釈して、1時間環流した。溶媒を濃縮して、酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、ブラインで洗浄して、乾燥して、オイルになるまで濃縮して、シリカゲルのカラムクロマトグラフィー(ジクロロメタン中、1−10%のメタノール)で精製することで、以下の物性値を有する透明な油状の標題化合物(0.119 g)を得た。
1H NMR (DMSO-d6): δ 4.52 (t, J = 5.2 Hz, 2H), 3.48-3.54 (m, 2H), 3.14 (d, J = 4.7 Hz, 2H), 3.04-3.09 (m, 2H), 1.38 (s, 9H), 1.31-1.36 (m, 2H), 1.11-1.19 (m, 2H), 0.86 (s, 3H);
マスデータ (APCI, Pos.): m/z 229 (M + H)+.
実施例417:
tert−ブチル 4−((4−アミノ−5−シアノ−6−エトキシピコリンアミド)メチル)−4−メチルピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 7.31 (br, 2H), 7.11 (s, 1H), 4.51 (t, J = 5.5 Hz, 1H), 4.37 (dd, J = 7.1, 14.1 Hz, 2H), 3.48-3.56 (m, 2H), 3.13-3.19 (m, 2H), 1.38 (s, 9H), 1.28-1.34 (m, 9H), 0.86 (s, 3H);
マスデータ (APCI, Pos.): m/z 419 (M + H)+.
実施例418:
4−アミノ−5−シアノ−6−エトキシ−N−((4−メチルピペリジン−4−イル)メチル)ピコリンアミド ビス−トリフルオロアセテート
1H NMR (DMSO-d6): δ 8.41 (br, 1H), 7.35 (br, 2H), 7.32 (s, 1H), 4.38 (q, J = 7.0 Hz, 2H), 4.13 (br, 2H), 4.25 (br, 2H), 3.03-3.17 (m, 4H), 1.63-1.71 (m, 2H), 1.48-1.56 (m, 2H), 1.32 (t, J = 7.0 Hz, 3H), 1.06 (s, 3H);
マスデータ (APCI, Pos.): m/z 319 (M + H)+.
実施例419:
4−アミノ−5−シアノ−6−エトキシ−N−((4−メチル−1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 8.61-8.63 (m, 1H), 8.08-8.10 (m, 1H), 7.92-7.97 (m, 1H), 7.80 (s, 1H), 7.45-7.48 (m, 1H), 7.37-7.32 (br, 2H), 7.11 (s, 1H), 4.71 (br, 1H), 4.39 (q, J = 7.0 Hz, 2H), 4.04 (s, 2H), 3.78 (s, 2H), 2.54-2.59 (m, 2H), 2.34-2.40 (m, 2H), 1.56-1.61 (m, 2H), 1.37-1.41 (m, 2H), 1.32 (t, J = 7.0 Hz, 3H), 1.01 (s, 3H);
マスデータ (APCI, Pos.): m/z 493 (M + H)+.
実施例420:
4−アミノ−5−クロロ−6−エトキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 8.61 (d, J = 4.7 Hz, 1H), 8.33 (t, J = 6.4 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.94 (td, J = 1.7, 7.7 Hz, 2H), 7.78 (s, 1H), 7.47 (ddd, J = 1.1, 4.8, 7.5 Hz, 1H), 7.09 (s, 1H), 6.50 (s, 1H), 4.45 (q, J = 7.0 Hz, 2H), 3.73 (s, 2H), 3.16 (t, J = 6.5 Hz, 2H), 2.85-2.88 (m, 2H), 1.97 (t, J = 10.7 Hz, 2H), 1.60-1.63 (m, 2H), 1.50-1.55 (m, 1H), 1.31 (t, J = 7.0 Hz, 3H), 1.15-1.24 (m, 2H);
マスデータ (APCI, Pos.): m/z 487 (M + H)+.
実施例421:
6−エトキシ−2−メチル−3−ニトロピリジン
1H NMR (DMSO-d6): δ 8.36 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.71 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
実施例422:
(E)−2−(6−エトキシ−3−ニトロピリジン−2−イル)−N,N−ジメチルエテンアミン
1H NMR (DMSO-d6): δ 8.19 (d, J = 9.1 Hz, 1H), 8.14 (d, J = 12.3 Hz, 1H), 6.31 (d, J = 12.3 Hz, 1H), 6.24 (d, J = 9.1 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 3.04 (br, 6H), 1.33 (t, J = 7.1 Hz, 3H).
実施例423:
6−エトキシ−3−ニトロピコリンアルデヒド
1H NMR (CDCl3): δ 10.32 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H);
マスデータ (APCI, Pos.): m/z 196 (M + H)+.
実施例424:
6−エトキシ−3−ニトロピコリン酸
1H NMR (DMSO-d6): δ 12.95 (br, 1H), 8.47 (d, J = 9.1 Hz, 1H), 7.10 (d, J = 9.1 Hz, 1H), 4.43 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 6.9 Hz, 3H);
マスデータ (APCI, Pos.): m/z 211 (M - H)-.
実施例425:
メチル 6−エトキシ−3−ニトロピコリネート
1H NMR (DMSO-d6): δ 8.52 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 9.2 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H), 3.98 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H);
マスデータ (APCI, Pos.): m/z 527 (M + H)+.
実施例426:
メチル 3−アミノ−6−エトキシピコリネート
1H NMR (DMSO-d6): δ 7.26 (d, J = 8.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 6.39 (br, 2H), 4.18 (q, J = 7.0 Hz, 2H), 3.78 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).
実施例427:
メチル 3−アミノ−4−クロロ−6−エトキシピコリネート
マスデータ (APCI, Pos.): m/z 231 (M + H)+.
実施例428:
3−アミノ−4−クロロ−6−エトキシピコリン酸
マスデータ (APCI, Pos.): m/z 215 (M - H)-.
実施例429:
3−アミノ−4−クロロ−6−エトキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.60 (d, J = 4.7 Hz, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.78 (br, 1H), 7.67 (s, 1H), 7.31-7.27 (m, 2H), 6.89 (s, 1H), 6.09 (br, 2H), 4.23 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H), 3.30 (d, J = 6.6 Hz, 2H), 2.97 (d, J = 11.5 Hz, 2H), 2.07 (t, J = 10.6 Hz, 2H), 1.74 (d, J = 12.2 Hz, 2H), 1.58-1.61 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.26 (br, 2H);
マスデータ (APCI, Pos.): m/z 487 (M + H)+.
実施例430:
メチル 3−アミノ−4,5−ジクロロ−6−エトキシピコリネート
3−アミノ−4,5−ジクロロ−6−エトキシピコリン酸
マスデータ (APCI, Pos.): m/z 249 (M - H)-.
実施例432:
3−アミノ−4,5−ジクロロ−6−エトキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CD3OD): δ 8.57 (d, J = 4.8 Hz, 1H), 8.26-8.35 (br, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.791 (t, J = 7.3 Hz, 1H), 7.79 (s, 1H), 7.43 (dd, J = 5.1, 7.4 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H), 3.94 (s, 2H), 3.33-3.29 (m, 2H), 3.08 (d, J = 11.6 Hz, 2H), 2.24 (t, J = 11.5 Hz, 2H), 1.80 (d, J = 13.1 Hz, 2H), 1.67-1.73 (m, 1H), 1.35-1.39 (m, 5H);
マスデータ (APCI, Pos.): m/z 523 (M + H)+.
実施例433:
4−メトキシ−2−フェノキシニコチノニトリル
1H NMR (DMSO-d6): δ 8.23 (d, J = 6.1 Hz, 1H), 7.47-7.43 (m, 2H), 7.27 (t, J = 7.4 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 6.1 Hz, 1H), 4.01 (s, 3H);
マスデータ (APCI, Pos.): m/z 227 (M + H)+.
実施例434:
4−フェノキシ−1H−ピラゾロ[4,3−c]ピリジン−3−アミン
1H NMR (DMSO-d6): δ 12.0 (br, 1H), 8.59 (br, 2H), 7.73 (d, J = 6.2 Hz, 1H), 7.43-7.39 (m, 2H), 7.23 (dd, J = 6.5, 13.8 Hz, 2H), 7.13 (d, J = 7.6 Hz, 1H), 6.81-6.69 (m, 1H);
マスデータ (APCI, Pos.): m/z 227 (M + H)+.
実施例435:
tert−ブチル 4−((4−フェノキシ−1H−ピラゾロ[4,3−c]ピリジン−3−イルアミノ)メチル)ピペリジン−1−カルボキシレート
1H NMR (DMSO-d6): δ 8.59 (br, 1H), 7.44-7.40 (m, 2H), 7.32 (d, J = 6.4 Hz, 1H), 7.25-7.22 (m, 2H), 6.70 (d, J = 6.4 Hz, 1H), 6.44 (br, 1H), 4.02 (d, J = 7.3 Hz, 2H), 3.95-3.91 (m, 2H), 2.71-2.64 (m, 2H), 2.13-2.07 (m, 1H), 1.52-1.49 (m, 2H), 1.39 (s, 12H), 1.19-1.11 (m, 2H);
マスデータ (APCI, Pos.): m/z 424 (M + H)+.
実施例436:
4−フェノキシ−N−(ピペリジン−4−イルメチル)−1H−ピラゾロ[4,3−c]ピリジン−3−アミノ ビス(2,2,2−トリフルオロアセテート)
1H NMR (DMSO-d6): δ 8.55 (br, 1H), 8.26 (br, 1H), 7.50-7.46 (m, 2H), 7.36 (d, J = 6.5 Hz, 1H), 7.31-7.28 (m, 3H), 6.81 (d, J = 6.5 Hz, 1H), 4.10 (d, J = 6.9 Hz, 2H), 3.29-3.26 (m, 2H), 2.90-2.82 (m, 2H), 2.23-2.19 (m, 1H), 1.75-1.72 (m, 2H), 1.47-1.39 (m, 2H);
マスデータ (APCI, Pos.): m/z 324 (M + H)+.
実施例437:
4−フェノキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−1H−ピラゾロ[4,3−c]ピリジン−3−アミン
1H NMR (DMSO-d6): δ 11.98 (br, 1H), 8.61 (d, J = 4.3 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.97-7.92 (m, 1H), 7.78 (s, 1H), 7.49-7.40 (m, 3H), 7.32 (d, J = 6.4 Hz, 1H), 7.25-7.20 (m, 3H), 6.70 (d, J = 6.4 Hz, 1H), 6.42 (br, 1H), 4.02 (d, J = 7.2 Hz, 2H), 3.74 (s, 2H), 3.17 (d, = 5.2 Hz, 2H), 2.89-2.87 (m, 2H), 1.99-1.93 (m, 2H), 1.54-1.51 (m, 1H), 1.38-1.28 (m, 2H);
マスデータ (APCI, Pos.): m/z 498 (M + H)+.
実施例438:
エチル 2−(2,6−ジフルオロフェニル)−4−メチルチアゾール−5−カルボキシレート
2−クロロアセトアセテート(42 mL)を室温で加えた。混合物を12時間環流して、冷却して、濃縮した。残渣をヘキサン(250 mL)を加え、30分間撹拌して、ろ過した後、ヘキサン(50 mL)で洗浄した。固体を乾燥して、以下の物性値を有する標題化合物(48.6 g)を得た。
1H NMR (CDCl3): δ 7.42 (m, 1H), 7.05 (m, 2H), 4.38 (q, J = 7.1 Hz, 2H), 2.82 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H);
実施例439:
エチル 2−(2,6−ジフルオロフェニル)−4−((ジメチルアミノ)メチル)チアゾール−5−カルボキシレート
この化合物(5.75 g)のテトラヒドロフラン(50 mL)溶液に2M ジメチルアミン テトラヒドロフラン(45 mL)溶液を加えた。混合物を室温で3時間撹拌した。混合物を飽和炭酸水素ナトリウム水溶液で希釈して、酢酸エチルで抽出した。合わせた有機層を硫酸ナトリウムで乾燥して、濃縮した。残渣をシリカゲルのカラムクロマトグラフィー(石油エーテル:酢酸エチル=5:1)で精製することで、以下の物性値を有する標題化合物(2.5 g)を得た。
1H NMR (d6-DMSO): δ 7.67 (m, 1H), 7.38-7.33 (m, 2H), 4.33 (q, J = 7.0 Hz, 2H), 3.96 (s, 2H), 2.24 (s, 6H), 1.32 (t, J = 7.0 Hz, 3H);
マスデータ (APCI, Pos.): m/z 327 (M + H)+.
実施例440:
2−(2,6−ジフルオロフェニル)−4−((ジメチルアミノ)メチル)チアゾール−5−カルバアルデヒド
1H NMR (d6-DMSO): δ 10.37 (s, 1H), 7.69 (m, 1H), 7.40-7.33 (m, 2H), 3.98 (s, 2H), 2.26 (s, 6H);
マスデータ (APCI, Pos.): m/z 283 (M + H)+.
実施例441:
4−アミノ−5−シアノ−N−((1−((2−(2,6−ジフルオロフェニル)−4−((ジメチルアミノ)メチル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミド
1H NMR (DMSO-d6): δ 8.46 (t, J = 6.3 Hz, 1H), 7.61-7.54 (m, 1H), 7.29 (s, 2H), 7.28 (t, J = 8.6 Hz, 2H), 7.04 (s, 1H), 4.47 (q, J = 7.0 Hz, 2H), 3.76 (s, 2H), 3.54 (s, 2H), 3.17 (t, J = 6.3 Hz, 2H), 2.92-2.86 (m, 2H), 2.16 (s, 6H), 2.05-1.98 (m, 2H), 1.64-1.59 (m, 2H), 1.58-1.52 (m, 1H), 1.31 (t, J = 7.0, 3H), 1.20-1.15 (m, 2H);
マスデータ (APCI, Pos.): m/z570.1 (M + H)+.
実施例442:
2−ヒドロキシ−6−メチル−5−ニトロニコチノニトリル:
1H NMR (DMSO-d6): δ 13.39 (s, 1H), 8.89 (s, 1H), 3.69 (s, 3H);
マスデータ (ESI, Neg.): m/z 178 (M - H)-.
実施例443:
2−クロロ−6−メチル−5−ニトロニコチノニトリル:
1H NMR (DMSO-d6): δ 9.21 (s, 1H), 2.81 (s, 3H);
マスデータ (ESI, Neg.): m/z 197 (M - H)-.
実施例444:
2−エトキシ−6−メチル−5−ニトロニコチノニトリル
1H NMR (CDCl3): δ 8.60 (s, 1H), 4.62 (q, J = 7.2 Hz, 2H), 2.85 (s, 3H), 1.50 (t, J = 7.2 Hz, 3H);
マスデータ (ESI, Neg.): m/z 206 (M - H)-.
実施例445:
6−(2−(ジメチルアミノ)ビニル)−2−エトキシ−5−ニトロニコチノニトリル
1H NMR (CDCl3): δ 8.52 (s, 1H), 8.08 (d, J = 12.4 Hz, 1H), 6.44 (d, J = 12.4 Hz, 1H), 4.50 (q, J = 7.2 Hz, 2H), 3.23 (broad s, 3H), 3.03 (broad s, 3H), 1.46 (t, J = 7.2 Hz, 3H);
マスデータ (ESI, Pos.): m/z 263 (M + H)+.
実施例446:
2−エトキシ−6−ホルミル−5−ニトロニコチノニトリル
1H NMR (CDCl3): δ 10.35 (s, 1H), 8.68 (d, J = 23.2 Hz, 1H), 4.72 (q, J = 7.2 Hz, 2H), 1.57 (t, J = 7.2 Hz, 3H);
マスデータ(ESI, Neg.): m/z 221 (M)-.
実施例447:
5−シアノ−6−エトキシ−3−ニトロピコリン酸
1H NMR (DMSO-d6): δ 9.19 (s, 1H), 4.58 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H);
マスデータ(ESI, Neg.): m/z 237 (M)-.
実施例448:
5−シアノ−6−エトキシ−3−ニトロ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 9.15 (s, 1H), 8.78 (t, J = 5.2 Hz, 1H), 8.61 (d, J = 4.4 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.49 (t, J = 5.2 Hz, 1H), 4.60 (q, J = 7.2 Hz, 2H), 3.75 (s, 2H), 3.17 (t, J = 6.0 Hz, 2H), 2.89 (t, J = 8.0 Hz, 2H), 2.00 (t, J = 10.8 Hz, 2H), 1.66 (d, J = 11.6 Hz, 2H), 1.57 (broad s, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.23 (m, 2H);
マスデータ (ESI, Pos.): m/z 508 (M + H)+.
実施例449:
3−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (CDCl3): δ 8.60 (d, J = 4.4 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.79 (m, 2H), 7.68 (s, 1H), 7.32 (m, 2H), 5.77 (broad s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 3.80 (broad s, 2H), 3.33 (t, J = 6.8 Hz, 2H), 2.99 (d, J = 10.8 Hz, 2H), 2.11 (t, J = 10.8 Hz, 2H), 1.76 (d, J = 12.0 Hz, 2H), 1.60 (broad s, 1H), 1.41 (m, 5H);
マスデータ (ESI, Pos.): m/z 478 (M + H)+.
実施例450:
5−シアノ−6−エトキシ−3−ニトロ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド
1H NMR (DMSO-d6): δ 9.13 (s, 1H), 8.81 (m, 1H), 7.90 (m, 2H), 7.53 (m, 2H), 6.95 (s, 1H), 4.61 (q, J = 7.2 Hz, 2H), 3.73 (broad s, 2H), 3.17 (m, 2H), 2.92 (m, 2H), 2.03 (t, J = 10.8 Hz, 2H), 1.71 (d, J = 12.0 Hz, 2H), 1.55 (broad s, 1H), 1.39 (t, J = 7.2 Hz, 3H), 1.22 (q, J = 10.8 Hz, 2H), 0.95 (d, J = 6.4 Hz, 1H);
マスデータ (ESI, Pos.): m/z 491 (M + H)+.
実施例451:
3−アミノ−5−シアノ−6−エトキシ−N−((1−((3−フェニルイソオキサゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド 塩酸塩
1H NMR (DMSO-d6): δ 10.82 (broad s, 1H), 8.55 (t, J = 6.4 Hz, 1H), 7.89 (d, J = 6.4 Hz, 2H), 7.67 (s, 1H), 7.56 (d, J = 4.4 Hz, 3H), 4.61 (broad s, 2H), 4.50 (broad s, 3H), 4.42 (q, J = 7.2 Hz, 2H), 3.49 (d, J = 11.6 Hz, 2H), 3.18 (t, J = 6.0 Hz, 2H), 3.02 (q, J = 10.8 Hz, 2H), 1.83 (d, J = 11.6 Hz, 3H), 1.57 (q, J = 11.6 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H);
マスデータ (ESI, Pos.): m/z 461 (M + H)+.
[生物学的実施例]
式(I)の本発明化合物は、抗糖尿病効果および神経保護効果を持つことは、例えば、以下の実験によって証明された。
[実験方法]
(1) DIO (diet-induced obese) マウスを用いた化合物の抗糖尿病効果の測定
本発明化合物の抗糖尿病効果は、以下の方法によって証明された。
試験期間中、マウスには高脂肪食(D12492, リサーチ ダイエッツ)を与えて、水は給水瓶から自由摂取させた。実験初日、尾静脈からマイクロキャピラリーを用いて採血をして、血糖値を測定した。血糖値を指標に、複数に群分け(1群あたり5匹を割り付け)を行ない、投薬を開始した。本発明化合物を事前に上記の媒体に懸濁後、強制的に経口で投与を行った。対照群には、媒体のみを投与した。投与開始から15日後、血漿のサンプルは尾静脈から終夜、絶食状態で採取した。血漿グルコースおよびインシュリンレベルは市販のキット(グルコース,グルコース CII−テスト ワコー(R),和光純薬工業株式会社;インシュリン,ラット インシュリンELISA キット,森永生科学研究所)を用いて測定した。
(2) ラット局所的脳虚血モデルを用いた化合物の神経保護効果の測定
一過性局所的脳虚血(120分間)は、Koizumiらの方法(日本のジャーナルであるストローク 1986;8:1−8)を用いて中大脳動脈(以下、MCAと略記)閉塞を誘発させた。雄のSprague-Dawleyラット(7週齢;チャールズ リバー ジャパン)を用いた。30%の酸素および70%の空気の条件下で、動物にハロタン吸入器(シナノ ワークス)を用いて、2.5%のハロタン(タケダ ケミカル インダストリーズ,エルティーディー)を吸入させた。麻酔下で、左総頸動脈(以下、CCAと略記)、外部頸動脈(以下、ECAと略記)および内頸動脈(以下、ICAと略記)を周辺の結合組織から、単離した後、CCAとECAを外科用糸で結紮した。シリコンでコートされた[キサントプレン VL プラス,(ヘレウス デンタル マテリアル,コー.,エルティーディー)およびオプトシル−キサントプレン アクティベーター(ヘレウス デンタル マテリアル,コー.,エルティーディー)の混合]ナイロンの縫合糸(約25 mm 長,4−0, ニッコー インダストリーズ,コー.,エルティーディー)をCCAを経由してICAに挿入した後、スギタ 動脈瘤クリップ(ミズホ コー.,エルティーディー)で左CCAを閉塞させた。2時間、MCA閉塞した後、麻酔下で再かん流させるためにナイロンの縫合糸を取り除いた。ヨネモリらの方法(ジェイ セレブ ブラッド フロウ メタブ 1996; 16: 973−80.参照)を用いて、動物の以前のMCA再かん流神経スコアをすぐに測定した。そして、スコアが5以下の動物は、再かん流が不十分なため、除外した。神経スコアは、尾懸垂試験(0:普通;1:穏やか;2:適度;3:激しい)における回転姿勢および、右下肢の牽引力の減少度(0:普通;1:穏やか;2:適度;3:激しい)の累積スコアに基づき測定した。本発明化合物またはビークル(0.5%メチル セルロース)を、MCA閉塞の1時間前とMCA閉塞の12時間後に、100mg/kg経口投与した。本発明化合物は0.5%メチル セルロースに懸濁した。
(2−1) 脳梗塞体積の評価方法
MCA再かん流24時間後に、神経スコアを測定した。脳を取りだし、両耳間から、ハンディ ブライン−スライサー(ブレインサイエンス アイデア.コー.,エルティーディー)を用いて、6つの断面になるよう2mmの幅で、脳をスライスした。
スライスしたものを2%の2,3,5−トリフェニルテトラゾリウム クロライド溶液に20−30分かけて染色して、ホルマリンで固定して、画像分析を行うまで保存した。画像のサンプルは、イメージアナライザー(MCID,イメージング リサーチ)を用いて、読み取りをした。
脳梗塞の面積は、スキャンした画像で同定し、スライスごとの梗塞領域を決定するために画像解析ソフト(フォトショップ 5.5/NIH イメージ 1.63)を使用して測定した。脳梗塞体積は、次の式を用いて推定された:
脳梗塞の体積(mm3)
=(6つの2mmのスライスの脳梗塞領域の合計)×2
脳梗塞体積は、皮質と皮質下部領域とで、別々に推測した。両範囲の合計した体積は、脳梗塞の合計した体積(脳半球)であると考えらる。
(3) ラットにおける化合物による肝障害の評価
肝毒性を評価するために、本発明化合物を、1群あたり4匹の雄のCrl:CD(SD)ラットに、0(対照群)および100mg/kgの用量で1日1回、4日間経口投与した。本発明化合物は、30%DMSO(ジメチルスルホキシド)を含有する70%ウェールソルブ(可溶化剤,セレステ コーポレーション)で溶解させて、10mL/kgの用量で経口投与した。対照群は、同じ投与量でビークルを投与した。
血液は、最終投与の翌日に、各動物の腹部静脈から採取した。血漿は、4℃で5分間で遠心分離(13684× g)により分離した。
肝障害の生化学的マーカーとして、血漿中のアスパラギン酸アミノトランスフェラーゼ濃度(AST)とアラニン アミノトランスフェラーゼ濃度(ALT)をそれぞれ測定した。
製剤例 1
下記の組成物を常法により混合して打錠して、一錠中に10mgの活性成分を含有する錠剤10,000錠を得た。
・4−クロロ−3−メトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド ……100 g
・カルボキシメチルセルロースカルシウム…(崩壊剤) ……20 g
・ステアリン酸マグネシウム…(滑沢剤) ……10 g
・微結晶セルロース …870 g
製剤例 2
下記の組成物を常法により混合した。溶液を常法により消毒して、除塵フィルターでろ過し、5mlずつアンプルに充填し、オートクレーブで加熱滅菌して、常法により凍結乾燥し、1アンプル中20mgの活性成分を含有するアンプル10,000本を得た。
・4−クロロ−3−メトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)ベンズアミド ……200 g
・マンニトール ……20 g
・蒸留水 ……50 L
Claims (6)
- 化合物が、
(1)4−アミノ−5−クロロ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド、
(2)4−アミノ−5−シアノ−6−エトキシ−N−({1−[(3−フェニル−5−イソオキサゾリル)メチル]−4−ピペリジニル}メチル)−2−ピリジンカルボキサアミド、
(3)4−アミノ−5−シアノ−6−エトキシ−N−((1−((2−(ピリジン−2−イル)チアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)ピコリンアミド、および
(4)4−アミノ−5−シアノ−N−((1−((4−((ジメチルアミノ)メチル)−2−フェニルチアゾール−5−イル)メチル)ピペリジン−4−イル)メチル)−6−エトキシピコリンアミドからなる群から選ばれる請求項1記載の化合物。 - 請求項1記載の式(I−1−5)の化合物、その塩、そのN−オキシドまたはその溶媒和物を含有する医薬組成物。
- 式(I−1−5)の化合物:
Cyc21は、メチルもしくはジメチルアミノメチル基を有していてもよいチアゾリルまたはイソオキサゾリルであり;
X1は、−CH2−、−CO−または−SO2−であり;
R10は、水素、メチル、ヒドロキシまたはメトキシ基であり;
W5は、CHまたはNであり;
R14は、シアノまたはアミノであり;
R15は、ハロゲン、シアノまたはアミノであり;および
R16は、C1−4のアルコキシである。)、その塩、そのN−オキシドまたはその溶媒和物の有効量を含有するインシュリン抵抗性糖尿病の予防および/または治療剤。
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GB0510139D0 (en) | 2005-05-18 | 2005-06-22 | Addex Pharmaceuticals Sa | Novel compounds B1 |
JP5084503B2 (ja) | 2005-07-29 | 2012-11-28 | 武田薬品工業株式会社 | シクロプロパンカルボン酸化合物 |
JP5324586B2 (ja) * | 2007-10-09 | 2013-10-23 | エフ.ホフマン−ラ ロシュ アーゲー | キラルシス−イミダゾリン |
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2010
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- 2010-01-07 US US13/143,998 patent/US8809538B2/en not_active Expired - Fee Related
- 2010-01-07 EP EP10729483.7A patent/EP2375899B1/en not_active Not-in-force
- 2010-01-07 WO PCT/US2010/020304 patent/WO2010080864A1/en active Application Filing
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US20110275608A1 (en) | 2011-11-10 |
US8809538B2 (en) | 2014-08-19 |
EP2375899B1 (en) | 2015-02-25 |
EP2375899A4 (en) | 2012-06-06 |
EP2375899A1 (en) | 2011-10-19 |
WO2010080864A1 (en) | 2010-07-15 |
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