JP6640978B2 - 6−(5−ヒドロキシ−1h−ピラゾール−1−イル)ニコチンアミド誘導体およびphd阻害剤としてのそれらの使用 - Google Patents
6−(5−ヒドロキシ−1h−ピラゾール−1−イル)ニコチンアミド誘導体およびphd阻害剤としてのそれらの使用 Download PDFInfo
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- JP6640978B2 JP6640978B2 JP2018245492A JP2018245492A JP6640978B2 JP 6640978 B2 JP6640978 B2 JP 6640978B2 JP 2018245492 A JP2018245492 A JP 2018245492A JP 2018245492 A JP2018245492 A JP 2018245492A JP 6640978 B2 JP6640978 B2 JP 6640978B2
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- Prior art keywords
- hydroxy
- pyrazol
- mmol
- title compound
- cyano
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- 239000003112 inhibitor Substances 0.000 title description 18
- 150000001875 compounds Chemical class 0.000 claims description 683
- 125000000217 alkyl group Chemical group 0.000 claims description 108
- -1 cyanomethyl Chemical group 0.000 claims description 105
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 74
- 229910052739 hydrogen Inorganic materials 0.000 claims description 69
- 239000001257 hydrogen Substances 0.000 claims description 69
- 125000003545 alkoxy group Chemical group 0.000 claims description 57
- 150000002431 hydrogen Chemical class 0.000 claims description 53
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
- 125000003282 alkyl amino group Chemical group 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- LMYGAQORWWQDEU-UHFFFAOYSA-N CC1=C(F)C(C#N)=CC=C1C1=C(O)N(C=2N=CC(=CC=2)C(=O)N2CCOCC2)N=C1 Chemical compound CC1=C(F)C(C#N)=CC=C1C1=C(O)N(C=2N=CC(=CC=2)C(=O)N2CCOCC2)N=C1 LMYGAQORWWQDEU-UHFFFAOYSA-N 0.000 claims description 2
- ZNFFKADYPCAFNM-UHFFFAOYSA-N CC1=CC(C#N)=C(F)C=C1C1=C(O)N(C=2N=CC(=CC=2)C(=O)N2CCOCC2)N=C1 Chemical compound CC1=CC(C#N)=C(F)C=C1C1=C(O)N(C=2N=CC(=CC=2)C(=O)N2CCOCC2)N=C1 ZNFFKADYPCAFNM-UHFFFAOYSA-N 0.000 claims description 2
- JBPTYBNPRQNNLE-UHFFFAOYSA-N OC1=C(C=2C=CC(=CC=2)C#N)C=NN1C(N=C1)=CC=C1C(=O)N1CCOCC1 Chemical compound OC1=C(C=2C=CC(=CC=2)C#N)C=NN1C(N=C1)=CC=C1C(=O)N1CCOCC1 JBPTYBNPRQNNLE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 238000005481 NMR spectroscopy Methods 0.000 description 457
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 186
- 239000007787 solid Substances 0.000 description 176
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 141
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 129
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 128
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 111
- JIVYBTARCYNEKS-UHFFFAOYSA-N CC1=CC(C#N)=CC=C1C1=C(O)N(C=2N=CC(=CC=2)C(O)=O)N=C1 Chemical compound CC1=CC(C#N)=CC=C1C1=C(O)N(C=2N=CC(=CC=2)C(O)=O)N=C1 JIVYBTARCYNEKS-UHFFFAOYSA-N 0.000 description 109
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 101
- 239000011541 reaction mixture Substances 0.000 description 97
- 235000019439 ethyl acetate Nutrition 0.000 description 88
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 86
- 238000002360 preparation method Methods 0.000 description 86
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 84
- 238000006243 chemical reaction Methods 0.000 description 78
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 229910052757 nitrogen Inorganic materials 0.000 description 68
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 67
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
- 125000005843 halogen group Chemical group 0.000 description 60
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 52
- 239000000243 solution Substances 0.000 description 51
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 49
- 239000000203 mixture Substances 0.000 description 49
- 125000001424 substituent group Chemical group 0.000 description 49
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 44
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 44
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 238000002953 preparative HPLC Methods 0.000 description 41
- 239000003921 oil Substances 0.000 description 39
- 229910052760 oxygen Inorganic materials 0.000 description 39
- 238000000034 method Methods 0.000 description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 35
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 30
- 125000000623 heterocyclic group Chemical group 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 150000001408 amides Chemical class 0.000 description 28
- 238000001914 filtration Methods 0.000 description 28
- XXTWMRQRJPLFIR-UHFFFAOYSA-N CC1=C(F)C(C#N)=CC=C1C1=C(O)N(C=2N=CC(=CC=2)C(O)=O)N=C1 Chemical compound CC1=C(F)C(C#N)=CC=C1C1=C(O)N(C=2N=CC(=CC=2)C(O)=O)N=C1 XXTWMRQRJPLFIR-UHFFFAOYSA-N 0.000 description 27
- 229910052717 sulfur Inorganic materials 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 25
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 25
- 239000012267 brine Substances 0.000 description 25
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 23
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 23
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 23
- 229910052799 carbon Inorganic materials 0.000 description 23
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 22
- GPICMFLAGYJRFF-UHFFFAOYSA-N N1=CC(C(=O)O)=CC=C1N1C(O)=C(C=2C=CC(=CC=2)C#N)C=N1 Chemical compound N1=CC(C(=O)O)=CC=C1N1C(O)=C(C=2C=CC(=CC=2)C#N)C=N1 GPICMFLAGYJRFF-UHFFFAOYSA-N 0.000 description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
- 229920006395 saturated elastomer Polymers 0.000 description 20
- 238000000746 purification Methods 0.000 description 19
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 238000003818 flash chromatography Methods 0.000 description 16
- 125000001072 heteroaryl group Chemical group 0.000 description 16
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 15
- 239000001301 oxygen Substances 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 13
- 206010021143 Hypoxia Diseases 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 12
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- RVHURNNPGLCJNE-UHFFFAOYSA-N C1=NC(OC)=CC(C2=C(N(N=C2)C=2N=CC(=CC=2)C(O)=O)O)=C1 Chemical compound C1=NC(OC)=CC(C2=C(N(N=C2)C=2N=CC(=CC=2)C(O)=O)O)=C1 RVHURNNPGLCJNE-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 208000007502 anemia Diseases 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 235000019253 formic acid Nutrition 0.000 description 11
- 238000002390 rotary evaporation Methods 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 10
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 10
- FXYGZLQLXKKXRC-UHFFFAOYSA-N 6-hydrazinyl-n-(oxan-4-ylmethyl)pyridine-3-carboxamide Chemical compound C1=NC(NN)=CC=C1C(=O)NCC1CCOCC1 FXYGZLQLXKKXRC-UHFFFAOYSA-N 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 10
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- 125000001153 fluoro group Chemical group F* 0.000 description 10
- 230000007954 hypoxia Effects 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 9
- BLVZYAOTUWCHKI-UHFFFAOYSA-N 6-(4-bromo-5-methoxypyrazol-1-yl)-N-(oxan-4-ylmethyl)pyridine-3-carboxamide Chemical compound COC1=C(Br)C=NN1C1=CC=C(C(=O)NCC2CCOCC2)C=N1 BLVZYAOTUWCHKI-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- LHVBNHYLRMKXMF-UHFFFAOYSA-N CC1=CC(C#N)=C(F)C=C1C1=C(O)N(C=2N=CC(=CC=2)C(O)=O)N=C1 Chemical compound CC1=CC(C#N)=C(F)C=C1C1=C(O)N(C=2N=CC(=CC=2)C(O)=O)N=C1 LHVBNHYLRMKXMF-UHFFFAOYSA-N 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 125000000753 cycloalkyl group Chemical group 0.000 description 9
- 230000000302 ischemic effect Effects 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- GQJDEHUTXDNEEG-UHFFFAOYSA-N 6-(4-bromo-5-methoxypyrazol-1-yl)-N-(3-methoxypropyl)pyridine-3-carboxamide Chemical compound N1=CC(C(=O)NCCCOC)=CC=C1N1C(OC)=C(Br)C=N1 GQJDEHUTXDNEEG-UHFFFAOYSA-N 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- 101150003085 Pdcl gene Proteins 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000000908 ammonium hydroxide Substances 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- SJVHOEXUUAOBTR-UHFFFAOYSA-N n-benzyl-6-hydrazinylpyridine-3-carboxamide Chemical compound C1=NC(NN)=CC=C1C(=O)NCC1=CC=CC=C1 SJVHOEXUUAOBTR-UHFFFAOYSA-N 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- BWKAYBPLDRWMCJ-UHFFFAOYSA-N 1,1-diethoxy-n,n-dimethylmethanamine Chemical compound CCOC(N(C)C)OCC BWKAYBPLDRWMCJ-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
- 239000007821 HATU Substances 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 7
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 7
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 208000028867 ischemia Diseases 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 6
- HDVKLNYOUYNFEY-UHFFFAOYSA-N COC1=CC(C#N)=CC=C1C1=C(O)N(C=2N=CC(=CC=2)C(O)=O)N=C1 Chemical compound COC1=CC(C#N)=CC=C1C1=C(O)N(C=2N=CC(=CC=2)C(O)=O)N=C1 HDVKLNYOUYNFEY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- C07D401/00—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
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Description
R1は、任意選択的に置換されたC1〜6アルキル、任意選択的に置換されたC3〜8シクロアルキル、および任意選択的に置換されたC3〜6ヘテロシクリルからなる群から選択され;
R2は、水素、C3〜8シクロアルキル、および任意選択的に置換されたC1〜4アルキルからなる群から選択され;
または
R1およびR2は、それらが付着する窒素と一緒になって、N、O、およびS群から独立して選択される1または2個の追加的な環状ヘテロ原子を任意選択的に有する4〜12員飽和環を形成し、いずれかの環炭素原子上で、シアノ、ハロ、ヒドロキシ、アミノ、C1〜12置換アミノ、任意選択的に置換されたC3〜6ヘテロシクリル、C1〜9アミド、任意選択的に置換されたC1〜6アルキル、およびC1〜4アルコキシからなる群から独立して選択される1〜5個の置換基で任意選択的に置換され、いずれかの追加的な環窒素上で、水素、任意選択的に置換されたC3〜8シクロアルキル、および任意選択的に置換されたC1〜6アルキルからなる群から独立して選択される置換基で置換され;
R3は、それぞれ水素、ヒドロキシル、アミノ、C1〜8アルキルアミノ、シアノ、ハロ、任意選択的に置換されたC1〜6アルキル、およびC1〜4アルコキシからなる群から独立して選択され;
R4は、水素、シアノ、ハロ、メチル、エチル、メトキシ、およびトリフルオロメチルからなる群から選択され;
R5は、
Gは炭素であり;
AはN、O、S、CR6、およびNR6からなる群から選択され;
EはN、O、S、およびCR6からなる群から選択され;
ただしAおよびEの1つだけがOまたはSであり得て;
またはGはNで、AおよびEはCR6であり;
またはGおよびAはNで、EはCR6であり;
またはG、A、およびEはNである)からなる群から選択され;
R6はそれぞれ、水素、シアノ、ハロ、C3〜8シクロアルキル、任意選択的に置換されたC1〜6アルキル、C1〜4アルコキシ、およびトリフルオロメチルからなる群から独立して選択され;
R7はシアノおよびシアノメチルからなる群から選択される)
の化合物、またはその薬学的に許容可能な塩を提供する。
を指す。
的に置換されたC1〜6アルキルを指す。
ミダゾリル、オキサゾリル、チアゾリル、ピラゾリル、トリアゾリル、ピリジル、およびピリミジルからなる群から選択される。
子質量と異なる原子質量を有する原子によって置き換えられている、全ての薬学的に許容可能な同位体のバリエーションもまた含む。式Iの化合物への包含に適する同位体としては、例えば、2Hおよび3Hなどの水素同位体;11C、13C、および14Cなどの炭素同位体;13Nおよび15Nなどの窒素同位体;15O、17O、および18Oなどの酸素同位体;35Sなどのイオウ同位体;18Fなどのフッ素同位体;および123Iおよび125Iなどのヨウ素同位体が挙げられる。同位体のバリエーション(例えば重水素2H)の使用は、より大きな代謝安定性をもたらしてもよい。さらに、本発明の化合物の特定の同位体のバリエーションに、薬物中で、および/または基質組織分布試験で有用であってもよい、放射性同位体(例えば、トリチウム、3H、または14C)を組み込んでもよい。11C、18F、15O、および13Nなどの陽電子放出同位体による置換は、基質受容体占有を調べるための陽電子放出微細構成(PET)試験で有用であってもよい。同位体的標識化合物は、非標識試薬の代わりに適切な同位体標識試薬を使用して、本開示の他の箇所で記載されるものと類似した方法によって調製されてもよい。
R1は、任意選択的に置換されたC1〜6アルキル、任意選択的に置換されたC3〜8シクロアルキル、および任意選択的に置換されたC3〜6ヘテロシクリルからなる群から選択され;
R2は、水素およびC1〜4アルキルからなる群から選択され;
または
R1およびR2は、それらが付着する窒素と一緒になって、N、O、およびS基から選択される追加的な環ヘテロ原子を任意選択的に有する4〜8員の飽和環を形成し、いずれかの環炭素原子上で、シアノ、ハロ、ヒドロキシ、アミノ、C1〜9アミド、C1〜4アルキル、C1〜4アルコキシ、ヒドロキシメチル、およびトリフルオロメチルからなる群から独立して選択される1〜5個の置換基で、任意選択的に置換され、いずれかの任意選択の追加的な環窒素上で、任意選択的に置換されたC1〜4アルキルで、任意選択的に置換され;
R3は、それぞれ水素、ヒドロキシル、アミノ、C1〜8アルキルアミノ、シアノ、ハロ、任意選択的に置換されたC1〜6アルキル、およびC1〜4アルコキシからなる群から独立して選択され;
R4は、水素、シアノ、ハロ、メチル、エチル、メトキシ、およびトリフルオロメチルからなる群から選択され;
R5は、
Gは炭素であり;
AはN、O、S、CR6、およびNR6からなる群から選択され;
EはN、O、S、およびCR6からなる群から選択され;
ただしAおよびEの1つだけがOまたはSであり得て;
またはGはNで、AおよびEはCR6であり;
またはGおよびAはNで、EはCR6であり;
またはG、A、およびEはNである)からなる群から選択され;
R6は、それぞれ、水素、シアノ、ハロ、任意選択的に置換されたC1〜6アルキル、C1〜4アルコキシ、およびトリフルオロメチルからなる群から独立して選択され;
R7はシアノおよびシアノメチルからなる群から選択される)
の化合物、またはその薬学的に許容可能な塩を提供する。
R1およびR2は、それらが付着する窒素と一緒になって、N、O、およびS群から独立して選択される1または2個の追加的な環状ヘテロ原子を任意選択的に有する4〜12員飽和環を形成し、いずれかの環炭素原子上で、シアノ、ハロ、ヒドロキシ、アミノ、C1〜12置換アミノ、任意選択的に置換されたC3〜6ヘテロシクリル、C1〜9アミド、任意選択的に置換されたC1〜6アルキル、およびC1〜4アルコキシからなる群から独立して選択される1〜5個の置換基で、任意選択的に置換され、いずれかの追加的な環窒素上で、水素、任意選択的に置換されたC3〜8シクロアルキル、および任意選択的に置
換されたC1〜6アルキルからなる群から独立して選択される置換基で置換され;
R3は、それぞれ水素、ヒドロキシル、アミノ、C1〜8アルキルアミノ、シアノ、ハロ、任意選択的に置換されたC1〜6アルキル、およびC1〜4アルコキシからなる群から独立して選択され;
R4は、水素、シアノ、ハロ、メチル、エチル、メトキシ、およびトリフルオロメチルからなる群から選択され;
R5は、
Gは炭素であり;
AはN、O、S、CR6、およびNR6からなる群から選択され;
EはN、O、S、およびCR6からなる群から選択され;
ただしAおよびEの1つだけがOまたはSであり得て;
またはGはNで、AおよびEはCR6であり;
またはGおよびAはNで、EはCR6であり;
またはG、A、およびEはNである)からなる群から選択され;
R6はそれぞれ、水素、シアノ、ハロ、C3〜8シクロアルキル、任意選択的に置換されたC1〜6アルキル、C1〜4アルコキシ、およびトリフルオロメチルからなる群から独立して選択され;
R7はシアノおよびシアノメチルからなる群から選択される)
の化合物、またはその薬学的に許容可能な塩を提供する。
qは、0、1、または2であり;
sは、0、1、または2であり;
R3は、それぞれ水素、ヒドロキシル、アミノ、C1〜8アルキルアミノ、シアノ、ハロ、任意選択的に置換されたC1〜6アルキル、およびC1〜4アルコキシからなる群から独立して選択され;
R4は、水素、シアノ、ハロ、メチル、エチル、メトキシ、およびトリフルオロメチルからなる群から選択され;
R5は、
Gは炭素であり;
AはN、O、S、CR6、およびNR6からなる群から選択され;
EはN、O、S、およびCR6からなる群から選択され;
ただしAおよびEの1つだけがOまたはSであり得て;
またはGはNで、AおよびEはCR6であり;
またはGおよびAはNで、EはCR6であり;
またはG、A、およびEはNである)からなる群から選択され;
R6はそれぞれ、水素、シアノ、ハロ、C3〜8シクロアルキル、任意選択的に置換されたC1〜6アルキル、C1〜4アルコキシ、およびトリフルオロメチルからなる群から独立して選択され;
R7はシアノおよびシアノメチルからなる群から選択され;
R8は、それぞれ、水素、シアノ、ハロ、C1〜4アルキル、C1〜4アルコキシ、およびトリフルオロメチルからなる群から独立して選択され;
R9は、水素、C1〜6アルキルで任意選択的に置換された1〜3フルオロ、およびC3〜8シクロアルキルからなる群から選択される)
の化合物、またはその薬学的に許容可能な塩を提供する。
qは、0、1、または2であり;
sは、0、1、または2であり;
R3は、それぞれ水素、ヒドロキシル、アミノ、C1〜8アルキルアミノ、シアノ、ハロ、任意選択的に置換されたC1〜6アルキル、およびC1〜4アルコキシからなる群から独立して選択され;
R4は、水素、シアノ、ハロ、メチル、エチル、メトキシ、およびトリフルオロメチルからなる群から選択され;
R5は、
Gは炭素であり;
AはN、O、S、CR6、およびNR6からなる群から選択され;
EはN、O、S、およびCR6からなる群から選択され;
ただしAおよびEの1つだけがOまたはSであり得て;
またはGはNで、AおよびEはCR6であり;
またはGおよびAはNで、EはCR6であり;
またはG、A、およびEはNである)からなる群から選択され;
R6はそれぞれ、水素、シアノ、ハロ、C3〜8シクロアルキル、任意選択的に置換されたC1〜6アルキル、C1〜4アルコキシ、およびトリフルオロメチルからなる群から独立して選択され;
R7はシアノおよびシアノメチルからなる群から選択され;
R10は、それぞれ、水素、シアノ、ハロ、ヒドロキシ、アミノ、C1〜12置換アミノ、任意選択的に置換されたC3〜6ヘテロシクリル、C1〜9アミド、任意選択的に置換されたC1〜6アルキル、およびC1〜4アルコキシからなる群から独立して選択され、水素、任意選択的に置換されたC3〜8シクロアルキル、および任意選択的に置換されたC1〜6アルキルからなる群から独立して選択される置換基で、いずれかの追加的な環窒素上で置換される)
の化合物、またはその薬学的に許容可能な塩を提供する。
R3は、それぞれ水素、ヒドロキシル、アミノ、C1〜8アルキルアミノ、シアノ、ハロ、任意選択的に置換されたC1〜6アルキル、およびC1〜4アルコキシからなる群から独立して選択され;
R4は、水素、シアノ、ハロ、メチル、エチル、メトキシ、およびトリフルオロメチルからなる群から選択され;
R5は、
Gは炭素であり;
AはN、O、S、CR6、およびNR6からなる群から選択され;
EはN、O、S、およびCR6からなる群から選択され;
ただしAおよびEの1つだけがOまたはSであり得て;
またはGはNで、AおよびEはCR6であり;
またはGおよびAはNで、EはCR6であり;
またはG、A、およびEはNである)からなる群から選択され;
R6はそれぞれ、水素、シアノ、ハロ、C3〜8シクロアルキル、任意選択的に置換されたC1〜6アルキル、C1〜4アルコキシ、およびトリフルオロメチルからなる群から独立して選択され;
R7はシアノおよびシアノメチルからなる群から選択され;
R8は、それぞれ、水素、シアノ、ハロ、C1〜4アルキル、C1〜4アルコキシ、およびトリフルオロメチルからなる群から独立して選択される)
の化合物、またはその薬学的に許容可能な塩を提供する。
)、(bc)、(c)、(ca)、(cb)、(d)、(da)、(db)、(e)、(ea)、(eb)、(f)、(fa)、(fb)、(g)、(h)、(i)、(j)、(ja)、(jb)、および(k)の化合物に関し、式中、R1は、C1〜4アルコキシ、C1〜9アミド、アミノ、C1〜8アルキルアミノ、C1〜5オキシカルボニル、シアノ、任意選択的に置換されたC3〜8シクロアルキル、ハロ、ヒドロキシ、いずれかの環窒素上でC1〜4アルキルで任意選択的に置換されたC3〜6ヘテロシクリル、C1〜10ヘテロアリール、および任意選択的に置換されたフェニルからなる群から独立して選択される1〜7個の置換基で、任意選択的に置換された、C1〜6アルキルである。
たC3〜8シクロアルキル、および任意選択的に置換されたC1〜6アルキルからなる群から選択される置換基で任意選択的に置換される。
、(ja)、(jb)、(u)、(v)、(ab)、および(ac)の化合物に関し、式中、R8の1つはC1〜6アルキルであり、他の各R8は水素である。
Chemistry(John Wiley and Sons,1991)で、標準的技法として理解される。式Iは、式1、2、3、4、および5を包含し、下の手順はまた、式1、2、3、4、および5の化合物を調製するのにも適するものと理解される。
)および水移動相による、または20/80(v/v)水/メタノール中の0.1%のギ酸(FA)による、または塩基性条件下の溶出、どちらも10mMのNH4HCO3を含有する、水および20/80(v/v)の水/アセトニトリル移動相による溶出;または酸性条件下の(XSelect(商標)C18、5μ、ID30×75mm)、0.1%のFAを含有するACNおよび水移動相による、または塩基性条件下の溶出、水中の0.1%水酸化アンモニウム(pH=9.5〜10)およびACN中の0.1%水酸化アンモニウム(pH=9.5〜10)による溶出をはじめとする、多様なシステムを使用して実施し得る。クロマトグラフィーによる単離後、溶媒を除去して、生成物含有画分を蒸発させることで、生成物を得る(例えば、GeneVac(商標))、回転蒸発器、排気フラスコ、凍結乾燥など。
THF(60.0mL)、亜鉛(19.61g、300mmol)、および塩化銅(I)(2.97g、30.0mmol)を窒素下で合わせた。撹拌される懸濁液を加熱して40分間還流させ、周囲温度に冷却し、エチル2−ブロモ酢酸(6.64mL、60mmol)を緩慢に添加した。反応を周囲温度でさらに1時間撹拌し、撹拌せずに一晩放置した。上部の透明な層を窒素下で別のフラスコにカニューレ装入して(cannulated)、表題化合物(約1M濃度)を得て、それをさらに精製せずに次の段階で使用した。
4−ブロモ−2−メトキシピリジン(654μl、5.32mmol)、(2−エトキシ−2−オキソエチル)亜鉛(II)臭化物(5850μl、5.85mmol)、およびPd(PPh3)4触媒(615mg、0.532mmol)をTHF(15.2mL)中で合わせて、電子レンジ内で120℃で5分間加熱した。反応物をコースガラスフリットを通して濾過し、濃縮して油にし、フラッシュクロマトグラフィー(ヘプタン中の5%〜50%EtOAcの勾配を使用する100gのシリカゲル)によって精製した。適切な画分を合わせて濃縮し、エチル2−(2−メトキシピリジン−4−イル)酢酸(400mg、38.5%の収率)を無色の油として得た。MSm/z[M+H]+196.1.
2−(2−メトキシピリジン−4−イル)酢酸エチル(320mg、1.639mmol)および1,1−ジエトキシ−N,N−ジメチルメタンアミン(2079μl、12.13mmol)を合わせて、100℃で1時間加熱し、次に撹拌しながら一晩周囲温度に冷却した。反応を真空濃縮し、褐色油を得た。油をEtOAcと水(200mL)の間で分配させた。水相をEtOAc(2×20mL)で逆抽出し、有機層を合わせて鹹水(100mL)で洗浄して、硫酸ナトリウム上で乾燥させ、真空濃縮して油にした。油をフラッシュクロマトグラフィー(ヘプタン中の5%〜50%EtOAcの勾配を使用する100gの塩基性シリカ)によって精製し、表題化合物を淡黄色油として得た。MSm/z[M+H]+251.1.
6−ヒドラジニルニコチン酸(167mg、1.090mmol)、3−(ジメチルアミノ)−2−(2−メトキシピリジン−4−イル)アクリル酸エチル(300mg、1.199mmol)、2−プロパノール(3632μl)、および塩酸(1.85%水性、2.15mL、1.090mmol)を合わせた。反応を室温で撹拌した。1時間後、ヒューニッヒ塩基(949μl、5.45mmol)を懸濁液に添加したところ、黄色溶液になった。反応物をEtOAc(2×15mL)で洗浄し、水相を真空濃縮して、黄色固体を得た。固体を1NのHCl(50mL)と共に摩砕し、濾過によって収集し水洗した
。次に固体をメタノール(2×60mL)およびジエチルエーテル(2×60mL)中でスラリーにし、真空乾燥して表題化合物を得た。MSm/z[M+H]+313.0.
2−(4−メトキシフェニル)酢酸(3.58mL、22.20mmol)および1,1−ジメトキシ−N,N−ジメチルメタンアミン(11.89mL、89mmol)を合わせて、100℃で14時間加熱した。反応を真空濃縮して淡黄色油を得て、フラッシュクロマトグラフィー(ヘプタン中の5%〜50%EtOAcの勾配を使用する100gの塩基性シリカによって精製し、表題化合物(361mg、6.91%)を無色の油として得た。MSm/z[M+H]+236.1.
1,4−ジオキサン(29.0mL)中の6−クロロニコチン酸(30.0g、189mmol)懸濁液をヒドラジン水和物(134mL、1.51mol)で処理して、90℃で一晩加熱した。混合物を周囲温度に冷却し、次に氷内で30分間冷却した。フラスコ側面のエッチングによって沈殿生成を誘発し、沈殿物を濾過して、激しく撹拌しながらEtOH(500mL)に再懸濁した。得られた懸濁液を濾過した。沈殿物を水(300mL)に溶解し、pH=1になるまでHCl(6N)を添加した。次にNaOH(水生50%)でpHを5に調節し、得られた懸濁液を1時間撹拌した。固体を濾過して収集し、真空乾燥して、表題化合物(16.65g、57.7%の収率)を灰白色固体として得た。1H NMR(400MHz,DMSO−d6)δppm6.70(d,1H)7.86(dd,J=8.97,2.15Hz,1H)8.32(br.s.,1H)8.52(d,J=1.77Hz,1H).MSm/z[M+H]+154.
6−ヒドラジニルニコチン酸(6.00g、39.2mmol)および2−(4−シアノフェニル)−3−(ジメチルアミノ)アクリル酸エチル(10.05g、41.1mmol)および2−プロパノール(80mL)を合わせて、1.85%塩酸(77mL、39.2mmol)で処理した。反応を室温で16時間撹拌し、次にヒューニッヒ塩基(34.1mL、196mmol)を懸濁液に添加して、均質にした。混合物を3時間撹拌した。反応混合物を酢酸イソプロピル(2×150mL)で洗浄した。合わせた有機層を水(40mL)で抽出し、合わせた水層を真空濃縮して、固体を得た。固体を1N HCl(300mL)と共に摩砕して、濾過して水洗し(20mL)、次にエタノール(350mL)中でスラリーにして、一晩顆粒化した。固体を濾過によって収集し、真空乾燥して、表題化合物(9.20g、77%の収率)を黄褐色固体として得た。1H NMR(400MHz,DMSO−d6)δppm7.79(d,J=8.34Hz,2H)8.14(br.s.,2H)8.47(d,J=7.07Hz,1H)8.71(br.s.,2H)8.97(s,1H)13.44(br.s.,1H)13.60(br.s.,1H).MS[M+H]307.
アセトン(9.28mL)中の1H−ピラゾール−4−カルボニトリル(0.432g、4.64mmol)、炭酸カリウム(1.924g、13.92mmol)、およびエチル2−ブロモ酢酸(1.027mL、9.28mmol)を合わせた。反応混合物を室温で一晩撹拌し、次に真空濃縮して、EtOAc(10mL)で希釈し、水洗(10mL)して乾燥(MgSO4)させ、真空濃縮して残渣を得た。シリカゲル(ヘプタン中のEtOAc、10〜50%勾配)上のフラッシュカラムクロマトグラフィーを使用して残渣を精製し、白色固体を得た。固体をヘプタンに懸濁し、次に濾過して乾燥させ、表題化合物(0.4314g、51.9%の収率)を白色固体として得た。1H NMR(400
MHz,DMSO−d6)δppm1.21(t,J=7.20Hz,3H)4.17(q,J=7.07Hz,2H)5.19(s,2H)8.11(s,1H)8.57(s,1H).MSm/z[M+H]+180.
2−(4−シアノ−1H−ピラゾール−1−イル)酢酸エチル(0.427g、2.383mmol)を1,1−ジエトキシ−N,N−ジメチルメタンアミン(1.403g、9.53mmol)と合わせて、閉じたバイアル内で100℃で2.5時間加熱した。混合物を真空濃縮し、NHシリカゲル(30gのSiO2、ヘプタン中のEtOAc、10〜50%の勾配)上のフラッシュカラムクロマトグラフィーを使用して精製し、表題化合物(0.4942g、89%の収率)を黄色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.12(t,3H)1.91−2.43(m,3H)2.70−3.29(m,3H)4.03(q,J=7.07Hz,2H)7.59(s,1H)8.14(s,1H)8.56(s,1H).MSm/z[M+H]+235
2−(4−フルオロフェニル)酢酸エチル(500mg、2.74mmol)を1,1−ジメトキシ−N,N−ジメチルメタンアミン(1.837mL、13.72mmol)およびDMF(2mL)中に合わせて、100℃で5時間加熱した。次に反応物をEtOAc(50mL)で希釈して、飽和水性塩化アンモニウム(50mL)および鹹水で洗浄し、硫酸マグネシウム上で乾燥させて、真空濃縮し、黄色油を得た。油を30gのNHシリカカラム(Moritex)上で精製し、ヘキサン誘導体中の0〜60%のEtOAcで溶出して、表題化合物(223mg、34.2%の収率)を無色透明な油として得た。1H NMR(400MHz,DMSO−d6)δppm1.10(t,J=7.1Hz,3H)2.64(s,6H)3.98(q,J=7.1Hz,2H)7.06−7.15(m,4H)7.49(s,1H).
表題化合物は、2−(4−シアノ−3−フルオロフェニル)酢酸メチルを使用して、例証的調製10と同様の方法で調製され、表題化合物が得られた。1H NMR(400MHz,DMSO−d6)δppm2.73(br.s.,6H)3.54(s,3H)7.11(dd,J=8.1,1.5Hz,1H)7.25(dd,J=11.1,1.5Hz,1H)7.63(s,1H)7.77(t,J=7.7Hz,1H).
表題化合物は、2−(4−(トリフルオロメチル)フェニル)酢酸エチルおよび1,1−ジエトキシ−N,N−ジメチルメタンアミンを使用して、例証的調製10と同様の方法で調製され、表題化合物が得られた。1H NMR(400MHz,クロロフォルム−d)δppm1.21(t,J=7.1Hz,3H)2.71(s,6H)4.14(q,J=7.2Hz,2H)7.31(d,J=7.8Hz,2H)7.53(d,J=7.8Hz,2H)7.61(s,1H).
表題化合物は、2−(4−オキソピリジン−1(4H)−イル)酢酸エチルおよび1,1−ジエトキシ−N,N−ジメチルメタンアミンを使用して、例証的調製10と同様の方法で調製され、表題化合物が得られた。MSm/z237[M+H]+.1HNMR(4
00MHz,DMSO−d6)δppm1.16(t,J=7.1Hz,3H)2.86(br.s,6H)4.06(q,J=7.1Hz,2H)6.01−6.11(m,2H)7.43−7.47(m,2H)7.48(s,1H).
3−ブロモベンゾニトリル(1500mg、8.24mmol)、0.5M(2−(tert−ブトキシ)−2−オキソエチル)亜鉛(II)塩化物(24.72mL、12.36mmol)、2’−(ジシクロヘキシルホスフィノ)−N,N−ジメチル−[1,1’−ビフェニル]−2−アミン(324mg、0.824mmol)、およびPd(dba)2(237mg、0.412mmol)をTHF(25mL)中で合わせて、油浴内で100℃で14時間加熱した。反応溶液をセライト(登録商標)上で濃縮し、120gのシリカゲルカラム上でクロマトグラフにかけて、ヘキサン誘導体中の0〜50%のEtOAcで溶出し、表題化合物(1.537g、86%の収率)を黄色油として得た。MSm/z218[M+H]+.1HNMR(400MHz,クロロフォルム−d)δppm1.45(s,9H)3.56(s,2H)7.40−7.46(m,1H)7.49−7.54(m,1H)7.54−7.59(m,2H).
2−(3−シアノフェニル)酢酸tert−ブチル(500mg、2.301mmol)、エタノール(10mL)、およびジオキサン(0.288mL、1.151mmol)中の4N HClを合わせて、溶液を60℃で22時間加熱した。溶液を真空濃縮し、表題化合物を黄色油として得て、それをさらに精製せずに使用した。MSm/z190[M+H]+.1HNMR(400MHz,クロロフォルム−d)δppm1.23−1.31(m,3H)3.65(s,2H)4.17(q,J=7.1Hz,2H)7.40−7.47(m,1H)7.51−7.56(m,1H)7.56−7.62(m,2H).
表題化合物は、2−(3−シアノフェニル)酢酸エチルおよび1,1−ジエトキシ−N,N−ジメチルメタンアミンを使用して、例証的調製10と同様の方法で調製され、表題化合物が得られた。1H NMR(400MHz,DMSO−d6)δppm1.12(t,J=7.1Hz,3H)2.67(s,6H)4.00(q,J=7.1Hz,2H)7.42−7.45(m,1H)7.45−7.50(m,1H)7.53−7.55(m,1H)7.57(s,1H)7.64(dt,J=7.1,1.7Hz,1H).
2−(4−(メチルスルホニル)フェニル)酢酸(1g、4.67mmol)をDCM(15mL)およびMeOH(5mL)中に合わせて、TMS−ジアゾメタン(ヘキサン誘導体中の2M)(3.50mL、7.00mmol)を緩慢に添加して、溶液を20℃で3時間撹拌した。反応物を酢酸(0.134mL、2.334mmol)でクエンチして15分間撹拌し、次に真空濃縮して表題化合物を得て、それをさらに精製せずに使用した。MSm/z229[M+H]+.
表題化合物は、2−(4−(メチルスルホニル)フェニル)酢酸メチルを使用して、例証的調製10と同様の方法で調製され、表題化合物が得られた。1H NMR(400MHz,DMSO−d6)δppm2.68(br.s.,6H)3.22(s,3H)3.53(s,3H)7.36(d,J=8.6Hz,2H)7.61(s,1H)7.80(d,J=8.6Hz,2H).
2−(2−オキソピリジン−1(2H)−イル)酢酸エチル(500mg、2.76mmol)、1,1−ジエトキシ−N,N−ジメチルメタンアミン(2031mg、13.80mmol)、およびDMF(2mL)を合わせて、100℃で15時間加熱した。反応混合物をキシレンで希釈してセライト(登録商標)上で濃縮し、次に30gのNHシリカカラム(Moritex)上で精製し、ヘキサン誘導体中の0〜100%のEtOAcで溶出し、表題化合物(551mg、85%の収率)を淡黄色固体として得た。MSm/z237[M+H]+.1HNMR(400MHz,DMSO−d6)δppm1.13(br.s.,3H)2.77(br.s.,6H)3.94−4.08(m,2H)6.17(td,J=6.7,1.3Hz,1H)6.36(dt,J=9.0,1.1Hz,1H)7.35−7.45(m,2H)7.47(s,1H).
3−メトキシプロパンニトリル(2.00g、23.50mmol)とTHF(75mL)を0℃で合わせ、次にチタン(IV)イソプロポキシド(7.57mL、25.9mmol)を添加し、それに続いてエチルマグネシウム臭化物(49.4mL、49.4mmol)を滴下して添加した。溶液を20℃で30分間撹拌し、次に三フッ化エーテル酸ホウ素(5.96mL、47.0mmol)を20℃で添加した(溶液は加熱して黒色になった)。混合物を40分間撹拌し、次に12mLの15%水酸化ナトリウム水溶液によって0℃でクエンチした。反応物を真空濃縮して残渣を得て、それを水で約100mLに希釈し、6×100mLのクロロホルムで抽出した。抽出物3〜6を硫酸マグネシウム上で乾燥させ、真空濃縮して、表題化合物(1.2g、44%の収率)を褐色油として得た。1H NMR(400MHz,クロロフォルム−d)δppm0.39−0.45(m,2H)0.53−0.60(m,2H)1.68(t,J=6.4Hz,2H)3.36(s,3H)3.59(t,J=6.4Hz,2H).
6−クロロニコチン酸(6.0g、38.1mmol)、HOBT(2.57g、19.04mmol)、およびEDC(10.95g、57.1mmol)をCH2Cl2(100mL)中で合わせて、ヒューニッヒ塩基(9.98mL、57.1mmol)および3−メトキシプロパン−1−アミン(5.85mL、57.1mmol)を添加して、20℃で22時間撹拌した。反応混合物を真空濃縮して残渣を得て、それをEtOAc(250mL)に取り込み、飽和水性塩化アンモニウム(250mL)および鹹水で洗浄し、硫酸マグネシウム上で乾燥させ、真空濃縮して残渣を得て、それを330gのシリカゲルカラム上で精製し、ヘキサン誘導体中の10〜80%のEtOAcで溶出して、表題化合物(6.6g、76%の収率)を白色固体として得た。MSm/z229,231[M+H]+.1HNMR(400MHz,DMSO−d6)δppm1.76(五重項,J=6.7Hz,2H)3.24(s,3H)3.27−3.35(m,2H)3.38(t,J=6.3Hz,2H)7.65(dd,J=8.3,0.8Hz,1H)8.23(dd,J=8.3,2.5Hz,1H)8.73(t,J=5.3Hz,1H)8.82(dd,J=2.5,0.8Hz,1H).
イソプロパノール(100mL)中の6−クロロ−N−(3−メトキシプロピル)ニコチンアミド(6.6g、28.9mmol)およびヒドラジン(4.53mL、144mmol)の溶液を80℃で21時間加熱した。ヒドラジン(3mL)をさらに添加して、加熱を80℃で24時間継続した。次に反応物を真空濃縮して、褐色油を得て、それをトルエンから再濃縮して、その塩酸塩としての表題化合物を白色固体として定量的収率で得
た。MSm/z225[M+H]+.1HNMR(400MHz,DMSO−d6)δppm1.66−1.78(m,2H)3.18−3.30(m,5H)3.35(t,J=6.3Hz,2H)6.68(d,J=8.8Hz,1H)7.87(dd,J=8.8,2.3Hz,1H)7.99(br.s.,1H)8.20(t,J=5.6Hz,1H)8.49(dd,J=2.4,0.6Hz,1H).
水(150mL)およびエタノール(25mL)中の6−ヒドラジニル−N−(3−メトキシプロピル)ニコチンアミド塩酸塩(7.5g、28.8mmol)、2−(エトキシメチレン)マロン酸ジエチル(14mL、69mmol)、および炭酸カリウム(9.94g、71.9mmol)の混合物を25℃で3時間撹拌し、次に60℃で18時間撹拌した。混合物を20℃に冷却して、濾過によって収集し、沈殿物を得て水洗し、表題化合物(8.14g、73.2%の収率)を黄色固体として得た。MSm/z349[M+H]+.1HNMR(400MHz,DMSO−d6)δppm1.19(t,J=7.1Hz,3H)1.77(五重項,J=6.7Hz,2H)3.25(s,3H)3.27−3.34(m,2H)3.38(t,J=6.3Hz,2H)4.02(q,J=7.1Hz,2H)7.52(s,1H)8.10(dd,J=8.8,2.5Hz,1H)8.42(dd,J=8.8,0.5Hz,1H)8.48(t,J=5.6Hz,1H)8.78(dd,J=2.4,0.6Hz,1H).
カリウム4−(エトキシカルボニル)−1−(5−((3−メトキシプロピル)カルバモイル)ピリジン−2−イル)−1H−ピラゾール−5−オラート(3.0g、7.76mmol)、飽和水性塩化アンモニウム(100mL)、および4N水性HCl(1.941mL、7.76mmol)の混合物を2時間撹拌して、黄色固体を得た。固体を濾過によって収集し、水洗して凍結乾燥機内で乾燥させて、表題化合物(2.228g、82%の収率)を黄色固体として得た。MSm/z349[M+H]+.
エチル5−ヒドロキシ−1−(5−((3−メトキシプロピル)カルバモイル)ピリジン−2−イル)−1H−ピラゾール−4−カルボン酸(2.2g、6.32mmol)、MeOH(5mL)、およびDCM(50mL)を合わせ、ヘキサン誘導体中の2.0MTMS−ジアゾメタン(4.42mL、8.84mmol)を(約10分間かけて)添加して、20℃で20分間撹拌した。次に反応物を酢酸(0.145mL、2.53mmol)でクエンチし、真空濃縮して残渣を得て、それを80gのシリカゲルカラム上で精製し、ヘキサン誘導体中の10〜100%EtOAcで溶出して、表題化合物(2.0g、87%の収率)を白色固体として得た。MSm/z363[M+H]+.1HNMR(400MHz,DMSO−d6)δppm1.30(t,J=7.1Hz,3H)1.78(五重項,J=6.6Hz,2H)3.25(s,3H)3.30−3.37(m,2H)3.39(t,J=6.3Hz,2H)4.14(s,3H)4.27(q,J=7.1Hz,2H)7.79(dd,J=8.5,0.6Hz,1H)8.03(s,1H)8.39(dd,J=8.5,2.4Hz,1H)8.76(t,J=5.6Hz,1H)8.98(dd,J=2.4,0.6Hz,1H).
5−メトキシ−1−(5−((3−メトキシプロピル)カルバモイル)ピリジン−2−
イル)−1H−ピラゾール−4−カルボン酸エチル(2.4g、6.62mmol)およびジオキサン(50mL)を合わせて、1.0Mの水性水酸化リチウム(29.8mL、29.8mmol)を添加して、混合物を20℃で2日間撹拌した。反応物を1N水性HCl(30mL)で酸性化して、クロロホルム(100mL、次に2×50mL)で抽出した。合わせた有機物を硫酸マグネシウム上で乾燥させ、真空濃縮して、表題化合物(2.195g、99%の収率)を灰白色固体として得た。MSm/z335[M+H]+.1HNMR(400MHz,DMSO−d6)δppm1.74(五重項,J=6.6Hz,2H)3.21(s,3H)3.30(q,J=6.7Hz,2H)3.36(t,J=6.3Hz,2H)4.10(s,3H)7.74(dd,J=8.5,0.6Hz,1H)7.94(s,1H)8.35(dd,J=8.5,2.4Hz,1H)8.72(t,J=5.6Hz,1H)8.94(dd,J=2.4,0.6Hz,1H)12.64(br.s.,1H).
5−メトキシ−1−(5−((3−メトキシプロピル)カルバモイル)ピリジン−2−イル)−1H−ピラゾール−4−カルボン酸(2.19g、6.55mmol)、NBS(1.749g、9.83mmol)、および炭酸水素ナトリウム(1.651g、19.65mmol)をDMF(20mL)中で合わせて、20℃で1時間撹拌した。反応物を水(100mL)で希釈し、EtOAc(100mL、次に2×50mL)で抽出した。合わせた有機物を鹹水で洗浄し、硫酸マグネシウム上で乾燥させ、真空濃縮して残渣を得て、それを120gのシリカゲルカラム上で精製し、ヘキサン誘導体中の10〜100%EtOAcで溶出して、表題化合物(2.348g、97%の収率)を白色固体として得た。MSm/z369,371[M+H]+.1HNMR(400MHz,DMSO−d6)δppm1.78(五重項,J=6.6Hz,2H)3.25(s,3H)3.30−3.37(m,2H)3.40(t,J=6.3Hz,2H)4.05(s,3H)7.79(dd,J=8.6,0.5Hz,1H)7.85(s,1H)8.38(dd,J=8.6,2.3Hz,1H)8.74(t,J=5.6Hz,1H)8.96(dd,J=2.4,0.6Hz,1H).
6−クロロニコチン酸(1.0g、6.35mmol)、4−(アミノメチル)ベンゾニトリル(1.007g、7.62mmol)、およびEDC(1.825g、9.52mmol)を塩化メチレン(50mL)中で合わせて、次にヒューニッヒ塩基(2.328mL、13.33mmol)を添加して、混合物を20℃で2時間撹拌した。4−(アミノメチル)ベンゾニトリル(250mg)、EDC(750mg)、およびヒューニッヒ塩基(1mL)をさらに添加して、撹拌を2日間継続した。反応物を真空濃縮して残渣を得て、それをEtOAc(100mL)に取り込み、飽和水性塩化アンモニウム(100mL)および鹹水で洗浄し、硫酸マグネシウム上で乾燥させて、真空濃縮して残渣を得て、それを80gのシリカゲルカラム上で精製し、ヘキサン誘導体中の0〜80%のEtOAcで溶出して、表題化合物(1.1g、63.8%の収率)を白色固体として得た。MSm/z272,274[M+H]+.1HNMR(400MHz,DMSO−d6)δppm4.58(d,J=6.1Hz,2H)7.53(d,J=8.6Hz,2H)7.68(dd,J=8.3,0.8Hz,1H)7.77−7.85(m,2H)8.28(dd,J=8.3,2.5Hz,1H)8.89(dd,J=2.5,0.5Hz,1H)9.40(t,J=5.7Hz,1H).
6−クロロ−N−(4−シアノベンジル)ニコチンアミド(500mg、1.840mmol)およびヒドラジン(0.578mL、18.40mmol)をイソプロパノール
(5mL)中で合わせて、90℃で5時間加熱した。上清をデカントし、真空濃縮して白色固体を得て、それを水(約10mL)と共に2時間激しく撹拌し、次に濾過して固体を乾燥させ、表題化合物(バッチ1、101mg)をピンク色の固体として得た。反応からの微細固体(上清の除去後)を水(約10mL)と共に2時間激しく撹拌し、次に濾過して凍結乾燥機内で乾燥させ、表題化合物(バッチ2、179mg)を黄褐色固体として得た。反応からの大型固形物(上清の除去後)を粉砕して、水(10mL)と共に1時間激しく撹拌し、次に濾過して、凍結乾燥機内で乾燥させて、表題(the title)(バッチ3、135mg)をベージュ固体として得た。合わせた収量は、415mg(84%の収率)であった。MSm/z268[M+H]+.
6−クロロニコチン酸(2.0g、12.69mmol)、(テトラヒドロ−2H−ピラン−4−イル)メタンアミン(2.193g、19.04mmol)、およびEDC(4.87g、25.4mmol)をCH2Cl2(100mL)中で合わせて、次にヒューニッヒ塩基(6.65mL、38.1mmol)を添加して、混合物を20℃で24時間撹拌した。(テトラヒドロ−2H−ピラン−4−イル)メタンアミン(1g、0.7当量)、ヒューニッヒ塩基(2.2mL、1当量)、およびDMAP(約10mg)をさらに添加して、反応物を45℃で18時間加熱した。ヒューニッヒ塩基(3mL)およびDMAP(80mg)をさらに添加して、加熱を50℃で5時間継続した。次に反応物を真空濃縮して残渣を得て、それをEtOAc(100mL)に取り込み、飽和水性塩化アンモニウム(100mL)および鹹水で洗浄して、硫酸マグネシウム上で乾燥させ、真空濃縮して残渣を得て、それを80gのシリカゲルカラム上で精製し、ヘキサン誘導体中の0〜100%EtOAcで溶出し、次に濾過して凍結乾燥機内で乾燥させて、表題化合物(0.985g、30.5%の収率)を白色固体として得た。MSm/z255,257[M+H]+.1HNMR(400MHz,DMSO−d6)δppm1.12−1.28(m,2H)1.60(dd,J=12.9,1.8Hz,2H)1.78(td,J=7.4,3.7Hz,1H)3.13−3.20(m,2H)3.26(td,J=11.7,2.1Hz,2H)3.84(dd,J=11.4,2.5Hz,2H)7.64(dd,J=8.3,0.5Hz,1H)8.23(dd,J=8.3,2.5Hz,1H)8.74(t,J=5.6Hz,1H)8.82(dd,J=2.5,0.8Hz,1H).
6−クロロ−N−((テトラヒドロ−2H−ピラン−4−イル)メチル)ニコチンアミド(828mg、3.25mmol)およびヒドラジン(0.510mL、16.25mmol)をイソプロパノール(10mL)中で合わせて、80℃で22時間加熱した。20℃に冷却して、2日後に白色沈殿物が成形し、それを濾過によって収集し、イソプロパノールで洗浄して真空乾燥し、HCl塩としての表題化合物(322mg)を白色固体として得た。第2の収穫物を濾液(500mg)から収集した。合わせた収量は、822mg(88%)であった。MSm/z251[M+H]+.1HNMR(400MHz,DMSO−d6)δppm1.09−1.26(m,2H)1.57(dd,J=12.9,1.8Hz,2H)1.75(dtt,J=14.9,7.5,7.5,3.4,3.4Hz,1H)3.11(t,J=6.3Hz,2H)3.19−3.31(m,2H)3.83(dd,J=11.4,2.5Hz,2H)4.26(br.s.,2H)6.68(d,J=8.8Hz,1H)7.87(dd,J=8.8,2.3Hz,1H)7.97(s,1H)8.18(t,J=5.7Hz,1H)8.49(d,J=1.8Hz,1H).
メチル6−(4−ブロモ−5−メトキシ−1H−ピラゾール−1−イル)ニコチン酸(1.0g、3.20mmol)、3−フルオロ−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)ベンゾニトリル(1.583g、6.41mmol)、ジクロロ[1,1’−ビス(ジ−t−ブチルホスフィノ)フェロセン]パラジウム(II)(0.209g、0.320mmol)、および炭酸水素ナトリウム(1.346g、16.02mmol)をジオキサン(10mL)および水(2.5mL)中で合わせて、電子レンジ内で110℃で30分間加熱した。反応物をEtOAcで希釈して、セライト(登録商標)上で濃縮し、100gのNHカラム(Moritex)上で精製して、ヘキサン誘導体中の10〜80%EtOAcで溶出し、表題化合物(1.0g)を得て、それをさらに精製せずに使用した。MSm/z353[M+H]+.1HNMR(400MHz,DMSO−d6)δppm3.90(s,3H)3.92(s,3H)7.81(dd,J=8.1,1.8Hz,1H)7.89−7.98(m,2H)8.00(dd,J=10.7,1.6Hz,1H)8.09(d,J=3.0Hz,1H)8.51(dd,J=8.6,2.3Hz,1H)9.08(dd,J=2.3,0.5Hz,1H).
上の調製からの生成物、6−(4−(4−シアノ−2−フルオロフェニル)−5−メトキシ−1H−ピラゾール−1−イル)ニコチン酸メチル(300mg、0.638mmol)、および塩化リチウム(135mg、3.19mmol)を無水N−メチル−2−ピロリジノン(5mL)中で合わせて、60℃で16時間加熱した。次に1.0Mの水性水酸化リチウム(3mL、3.00mmol)を添加して、20℃で4時間撹拌した。次に反応混合物を1N水性HCl(5mL)で酸性化して、黄色沈殿物を形成させた。沈殿物を濾過によって収集し、水洗して、高真空(約10Pa)下で乾燥させて、0.9当量のN−メチル−2−ピロリジノンを含有する表題化合物(230mg、定量的収率)を褐色固体として得た。MSm/z325[M+H]+.1HNMR(400MHz,DMSO−d6)δppm7.65(dd,J=8.2,1.6Hz,1H)7.80(dd,J=11.7,1.6Hz,1H)8.24(br.s.,1H)8.38−8.44(m,1H)8.52(br.s.,2H)8.87−8.94(m,1H)13.40(br.s.,1H).
4−ブロモ−3−フルオロベンゾニトリル(2.0g、10.00mmol)、Pd(dba)2(0.287g、0.500mmol)、および2’−(ジシクロヘキシルホスフィノ)−N,N−ジメチル−[1,1’−ビフェニル]−2−アミン(0.394g、1.000mmol)を窒素パージしながらTHF(60mL)中で合わせた。次にシリンジを通じて、(2−(tert−ブトキシ)−2−オキソエチル)亜鉛(II)塩化物(0.5M、30mL、15.0mmol)を添加した。反応混合物を50℃の油浴内で18時間加熱し、次にシリカゲル(11g)に吸着させて、80gのシリカゲルカラム(シングルステップ(商標))上で、1:1のヘプタン/EtOAc溶出剤を使用するフラッシュクロマトグラフィーによって精製して、残渣を得た。残渣をトルエン(0.5mL)に溶解し、80gのシリカゲルカラム(シングルステップ(商標))上で、ヘプタン/EtOAc(0〜25%EtOAc)の勾配溶出剤を使用するフラッシュクロマトグラフィーによって精製し、表題化合物(1.752g、74.5%の収率)を黄色固体として得た。1H NMR(400MHz,クロロフォルム−d)δppm1.45(s,9H)3.64(d,J=1.26Hz,2H)7.36(dd,J=8.97,1.39Hz,1H)7.40(d,J=7.07Hz,1H)7.42−7.45(m,1H)
.MSm/z[M+H]+236.1.
2−(4−シアノ−2−フルオロフェニル)酢酸tert−ブチル(227.3mg、0.966mmol)をEtOH(5mL)と合わせて、ジオキサン中の4M塩化水素溶液(0.121mL、0.483mmol)を添加して、加熱ブロック内で60℃で16時間撹拌した。次に反応混合物を回転蒸発を通じて濃縮し、EtOH(5mL)で戻した。ジオキサン中の4M塩化水素溶液(17.61mg、0.483mmol)の追加量をバイアルに添加して、混合物を60℃でさらに1時間撹拌した。次に反応混合物を回転蒸発を通じて濃縮し、真空乾燥して、表題化合物(198mg、99%の収率)を黄色油として得た。1H NMR(400MHz,クロロフォルム−d)δppm1.27(t,J=7.07Hz,3H)3.72(d,J=1.26Hz,2H)4.19(q,J=7.24Hz,2H)7.36−7.40(m,1H)7.40−7.43(m,1H)7.43−7.46(m,1H).MSm/z[M+H]+208.0.
表題化合物は、2−(4−シアノ−2−フルオロフェニル)酢酸エチルおよび1,1−ジエトキシ−N,N−ジメチルメタンアミンを使用して、例証的調製物10と同様の方法で調製され、表題化合物を得た。1H NMR(400MHz,DMSO−d6)δppm1.10(t,J=7.07Hz,3H)2.71(br.s.,6H)4.00(五重項,J=6.76Hz,2H)7.37(t,J=7.71Hz,1H)7.60(dd,J=7.96,1.64Hz,1H)7.64(s,1H)7.75(dd,J=9.47,1.64Hz,1H).MSm/z[M+H]+236.2,263.2.
6−ヒドラジニル−N−((テトラヒドロ−2H−ピラン−4−イル)メチル)ニコチンアミド(1.0g、4.00mmol)および炭酸カリウム(2.209g、15.98mmol)を水(25mL)中で合わせて、2−(エトキシメチレン)マロン酸ジエチル(0.807mL、4.00mmol)を23℃で添加した。反応混合物を100℃で14時間撹拌し、次に3NのHCl(10mL、7.5当量)を添加して褐色の懸濁液を得た。固体を濾過して水洗(3×5mL)し、真空乾燥して、表題化合物(1.114g、74.5%の収率)を黄色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.15−1.24(m,2H)1.26(t,J=7.07Hz,3H)1.56−1.68(m,2H)1.81(qdd,J=11.16,11.16,11.16,6.95,3.79Hz,1H)3.19(t,J=6.32Hz,2H)3.27(td,J=11.75,2.02Hz,2H)3.82−3.90(m,2H)4.18(q,J=7.24Hz,2H)8.12(br.s.,1H)8.13−8.24(m,1H)8.46(dd,J=8.84,2.27Hz,1H)8.76(t,J=5.68Hz,1H)8.89(dd,J=2.27,0.76Hz,1H)13.73(br.s.,1H).MSm/z[M+H]+329.3,375.4.
5−ヒドロキシ−1−(5−(((テトラヒドロ−2H−ピラン−4−イル)メチル)カルバモイル)ピリジン−2−イル)−1H−ピラゾール−4−カルボン酸エチル(0.6g、1.603mmol)、EtOAc(30mL)、およびMeOH(10mL)を合わせ、次にヘキサン誘導体中の2.0M溶液の(ジアゾメチル)トリメチルシラン(2
.60mL、5.21mmol)を23℃で20分間かけて添加した。反応混合物を23℃で1時間撹拌し、酢酸(0.206mL、3.61mmol)でクエンチして、混合物23℃で2時間撹拌した。反応混合物を濃縮して橙褐色油を得て、それを25gのシリカゲルカラム(シングルステップ(商標))上で、100%EtOAc溶出剤を使用する中圧クロマトグラフィーによって精製し、表題化合物(408mg、65.5%の収率)を灰白色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.16−1.27(m,2H)1.31(t,J=7.07Hz,3H)1.62(dd,J=12.88,2.02Hz,2H)1.81(ttd,J=11.13,11.13,7.31,7.31,3.79Hz,1H)3.20(t,J=6.44Hz,2H)3.27(td,J=11.68,2.15Hz,2H)3.85(dt,J=9.35,2.27Hz,2H)4.14(s,3H)4.27(q,J=7.07Hz,2H)7.79(dd,J=8.34,0.76Hz,1H)8.03(s,1H)8.38−8.43(m,1H)8.78(t,J=5.81Hz,1H)8.98(dd,J=2.53,0.76Hz,1H).MSm/z[M+H]+389.4.
5−メトキシ−1−(5−(((テトラヒドロ−2H−ピラン−4−イル)メチル)カルバモイル)ピリジン−2−イル)−1H−ピラゾール−4−カルボン酸エチル(401mg、1.032mmol)、ジオキサン(7mL)、および1M水性LiOH(5.16mL、5.16mmol)を23℃で合わせた。反応混合物を23℃で3時間撹拌し、次に1N HCl(水性)(5.16mL、5.16mmol)でクエンチして、回転蒸発を通じて濃縮し、灰白色懸濁液を得た。懸濁液を濾過して水洗(5×3mL)し、真空乾燥して、表題化合物(339.8mg、91%の収率)を白色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.16−1.28(m,2H)1.58−1.67(m,2H)1.75−1.88(m,1H)3.20(t,J=6.32Hz,2H)3.27(td,J=11.62,2.02Hz,2H)3.82−3.90(m,2H)4.14(s,3H)7.78(dd,J=8.59,0.76Hz,1H)7.98(s,1H)8.40(dd,J=8.46,2.40Hz,1H)8.78(t,J=5.81Hz,1H)8.98(dd,J=2.40,0.63Hz,1H)12.68(s,1H).MSm/z[M+H]+361.4.
5−メトキシ−1−(5−(((テトラヒドロ−2H−ピラン−4−イル)メチル)カルバモイル)ピリジン−2−イル)−1H−ピラゾール−4−カルボン酸(329.5mg、0.914mmol)および炭酸水素ナトリウム(307mg、3.66mmol)をDMF(3mL)中で合わせて、次に1−ブロモピロリジン−2,5−ジオン(163mg、0.914mmol)を23℃で添加した。反応混合物を23℃で30分間撹拌し、次に水(15mL)で希釈して、懸濁液を得た。懸濁液を濾過して水洗(3×5mL)し、真空乾燥して、表題化合物(302mg、84%の収率)を白色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.15−1.28(m,2H)1.62(dd,J=12.88,1.77Hz,2H)1.80(dddt,J=14.78,11.12,7.39,3.44,3.44Hz,1H)3.16−3.23(m,2H)3.23−3.31(m,2H)3.81−3.89(m,2H)4.05(s,3H)7.79(dd,J=8.59,0.76Hz,1H)7.84(s,1H)8.38(dd,J=8.46,2.40Hz,1H)8.75(t,J=5.81Hz,1H)8.96(dd,J=2.53,0.76Hz,1H).MSm/z[M+H]+395.3,397.3.
2−(ピリジン−4−イル)酢酸エチル(0.927mL、6.05mmol)および1,1−ジエトキシ−N,N−ジメチルメタンアミン(5.19mL、30.3mmol)をDMF(3.03mL)中で合わせて、100℃で6時間加熱した。反応混合物を濃縮し、50mLのジクロロメタンで希釈して、50mLの水で2回洗浄した。有機層を収集して、硫酸マグネシウム上で乾燥させ、濾過および濃縮して、残渣を得て、それを60gのNHシリカゲルカラム上で精製して、ヘキサン誘導体およびEtOAcで溶出し、表題化合物(1.333g、76%)を黄色油として得た。1H NMR(400MHz,クロロフォルム−d)δppm1.13(t,J=7.1Hz,3H)2.67(s,6H)4.06(q,J=7.1Hz,2H)6.98−7.12(m,2H)7.56(s,1H)8.29−8.53(m,2H).
(2−(tert−ブトキシ)−2−オキソエチル)亜鉛(II)塩化物(4.24mL、2.122mmol)および4−ブロモ−3−メトキシベンゾニトリル(0.30g、1.42mmol)をTHF(4.29mL)中で合わせて、次に2’−(ジシクロヘキシルホスフィノ)−N,N−ジメチル−[1,1’−ビフェニル]−2−アミン(0.056g、0.141mmol)およびPd(dba)2(0.041g、0.071mmol)を添加して、反応を100℃で一晩還流させた。反応混合物を回転蒸発によって濃縮し、シリカゲルカラム上で精製して、ヘキサン誘導体およびEtOAcで溶出し、表題化合物を黄色油として得た(102mg、29%)。MSm/z[M+H]+248.
2−(4−シアノ−2−メトキシフェニル)酢酸tert−ブチル(549mg、2.218mmol)、およびジオキサン中の4N HCl(0.277mL、1.109mmol)をエタノール(7.4mL)中で合わせて、60℃で16時間撹拌した。反応物を回転蒸発によって濃縮し、次に2−(4−シアノ−2−メトキシフェニル)酢酸エチル(0.486g、2.217mmol)および1,1−ジエトキシ−N,N−ジメチルメタンアミン(1.9mL、11.08mmol)と共にDMF(4.43mL)中で合わせて、100℃で16時間撹拌した。反応混合物を200mLのEtOAcで希釈して、200mLの水で2回洗浄した。有機層を硫酸ナトリウムで乾燥させて濃縮し、残渣を得て、それを60gのNHシリカゲルカラム上で精製し、ヘキサン誘導体およびEtOAcで溶出して、表題化合物(405mg、74%)を得た。
4−ブロモ−3−クロロベンゾニトリル(0.600g、2.77mmol)および(2−(tert−ブトキシ)−2−オキソエチル)亜鉛(II)塩化物(8.32mL、4.16mmol)をTHF(5.54mL)中で合わせて、次にPd(dba)2(0.080g、0.139mmol)および2’−(ジシクロヘキシルホスフィノ)−N,N−ジメチル−[1,1’−ビフェニル]−2−アミン(0.109g、0.277mmol)を添加して、反応を65℃で一晩還流させた。反応物を回転蒸発によって濃縮し、シリカゲルカラム上で精製して、ヘキサン誘導体およびEtOAcで溶出し、表題化合物(274mg、39%)を黄色油として得た。MSm/z[M+H]+252.
2−(2−クロロ−4−シアノフェニル)酢酸tert−ブチル(274mg、1.089mmol)、およびジオキサン中の4N HCl(0.136mL、0.544mmol)をエタノール(2.51mL)中で合わせた。混合物を60℃で16時間撹拌し、
次に回転蒸発によって濃縮し、2−(2−クロロ−4−シアノフェニル)酢酸エチル(0.243g、1.086mmol)および1,1−ジエトキシ−N,N−ジメチルメタンアミン(0.931mL、5.43mmol)と共にDMF(2.173mL)中で合わせて、100℃で16時間撹拌した。反応物を回転蒸発中で濃縮して、NHシリカゲルカラム上で精製し、ヘキサン誘導体およびEtOAcで溶出して、表題化合物(164mg,54%)を黄色油として得た。1H NMR(400MHz,クロロフォルム−d)δppm1.04−1.29(m,1H)3.96−4.31(m,1H)7.38(d,J=7.8Hz,1H)7.49(dd,J=7.8,1.8Hz,1H)7.63−7.71(m,1H).
テトラヒドロ−2H−ピラン−4−カルボニトリル(1.000g、9.00mmol)およびチタン(IV)イソプロポキシド(2.90mL、9.90mmol)をエーテル(45.0mL)中で合わせて、次にエチルマグネシウム臭化物(6.60mL、19.79mmol)を添加して、反応物が室温になるまで1時間放置した。反応物をさらに30分間撹拌して、三フッ化エーテル酸ホウ素(2.280mL、18.0mmol)を添加し、反応物を2時間撹拌した。次に反応物を10mLの水および20mLの1N HClで希釈して、200mLのEtOAcで2回抽出した。有機層を合わせて濃縮し、表題化合物(850mg、53.5%)を黄色油として得た。
2−(4−シアノ−2−メトキシフェニル)−3−(ジメチルアミノ)アクリル酸エチル(1.427g、5.20mmol)、6−ヒドラジニルニコチン酸(0.664g、4.34mmol)、およびHCl(4.34mL、4.34mmol)を2−プロパノール(21.7mL)中で合わせて、室温で8時間撹拌して固体を得た。固体を濾過によって収集し、ヒューニッヒ塩基(1.50mL、8.61mmol)と共に、2−プロパノール(10mL)および水(1mL)中で合わせて、50℃で32時間撹拌し、次に10mLの1N HClを添加して反応物を濾過し、固体を得た。固体を30mLのMeOHおよび30mLのエーテルで洗浄し、真空乾燥して、表題化合物(708mg、73.3%)をベージュの固体として得た。MSm/z[M+H]+337.3.
6−クロロニコチン酸(20g、12.74mmol)およびHATU(72.6g、19.1mmol)をDMF(200mL)中で合わせて、トリエチルアミン(38.6g、38.2mmol)を滴下して添加し、ベンジルアミン(16.36g、15.28mmol)がそれに続いて、室温で一晩撹拌した。次に反応混合物を氷水中に注ぎ入れ、20分間撹拌して固体を得た。固体を濾過によって収集し、水洗(30mL×2)して減圧下で乾燥させ、表題化合物(20g、64%)を黄色固体として得た。
N−ベンジル−6−クロロニコチンアミド(13g、52.8mmol)およびエタノール(60mL)を合わせて、次にヒドラジン水和物(85%、30mL)を室温で滴下して添加した。添加後、溶液を加熱して、一晩還流させた。次に反応混合物を濃縮してエタノールを除去し、固体を得た。固体を濾過によって収集し、EtOAc(3×20mL)で洗浄して減圧下で乾燥させ、表題化合物(10g、78%)をオフイエローの固体として得た。
2−(4−シアノフェニル)酢酸エチル(25g、0.132mol)をDMF−DE
A(60mL)と合わせて、70℃で3時間加熱した。反応混合物を室温に冷却して濃縮し、次にフラッシュクロマトグラフィーによって精製し、表題化合物(20g、62%)を固体として得た。1H NMR(400MHz,DMSO−d6)δppm7.71(d,J=8.4Hz,2H),7.59(s,1H),7.29(d,J=8.4Hz,2H),4.03(q,J=6.8Hz,2H),2.67(s,6H),1.13(t,J=6.8Hz,3H).
5−ブロモ−2−クロロ−4−メチルピリジン(15.0g、72.46mmol)およびEtOH(60mL)を合わせて、ヒドラジン水和物(85%、45mL)を添加して、120℃で一晩撹拌した。反応混合物を濃縮して残渣を得て、それをEtOAc(50mL×2)および水(50mL×2)で抽出した。次に合わせた有機層を鹹水で抽出して、Na2SO4上で乾燥させて濃縮し、残渣を得て、それをフラッシュクロマトグラフィー(石油エーテル:EtOAc=10:1〜1:5)によって精製し、表題化合物(7.8g、53%)を得た。
5−ブロモ−2−ヒドラジニル−4−メチルピリジン(6.0g、29.85mmol)およびイソプロパノール(100mL)を合わせて、2−(4−シアノフェニル)−3−(ジメチルアミノ)アクリル酸エチル(8.02g、32.84mmol)およびHCl溶液(水性、1.85%、49.75mL)を添加して、室温で2時間撹拌し、次にDIEA(19.40g、149.25mmol)を添加した。約30分後に、反応物を蒸発させて残渣を得て、それをEtOAc(50mL×2)および水(50mL×2)で抽出し、EtOAc層を合わせて鹹水で洗浄し、Na2SO4上で乾燥させて残渣を得て、それをフラッシュクロマトグラフィー(石油エーテル:EtOAc 5:1〜1:8)によって精製し、表題化合物(8.67g、82.04%)を得た。
4−(1−(5−ブロモ−4−メチルピリジン−2−イル)−5−ヒドロキシ−1H−ピラゾール−4−イル)ベンゾニトリル(8.67g、24.49mmol)、THF(100mL)、(トリメチルシリル)エトキシ)メチル塩化物(8.91g、48.98mmol)、およびトリエチルアミン(7.42g、73.47mmol)を合わせて、室温で3時間撹拌した。次に反応混合物を真空蒸発させて、残渣をEtOAc(100mL×2)および水(100mL×2)で抽出し、EtOAc層を鹹水で洗浄して、Na2SO4上で乾燥させ、蒸発させて残渣を得て、それをシリカゲル上のフラッシュクロマトグラフィー(石油エーテル:EtOAc 10:1〜1:3)によって精製し、表題化合物(10.5g、88.2%)を得た。
4−(1−(5−ブロモ−4−メチルピリジン−2−イル)−5−((2−(トリメチルシリル)エトキシ)メトキシ)−1H−ピラゾール−4−イル)ベンゾニトリル(10.0g、20.66mmol)、DMF(60mL)およびMeOH(60mL)を合わせて、次にトリエチルアミン(6.26g、61.98mmol)およびPd(dppf)Cl2(756.2mg、1.033mmol)を添加した。混合物を1MPaのCO下で、120℃で一晩撹拌した。次に反応混合物を真空蒸発させて残渣を得て、それを水と合わせて濾過し、水性(aqueous)をEtOAc(100mL×2)で抽出した
。合わせたEtOAc層を鹹水で洗浄し、乾燥させて濃縮し(Na2SO4)、表題化合物(8.67g)を得た。
6−(4−(4−シアノフェニル)−5−((2−(トリメチルシリル)エトキシ)メトキシ)−1H−ピラゾール−1−イル)−4−メチルニコチン酸メチル(8.67g、25.96mmol)、メタノール(50mL)、水(50mL)、およびLiOH(3.27g、77.87mmol)を合わせた。反応混合物を室温で6時間、そして50℃で一晩、撹拌した。反応混合物を濃縮して、メタノールの大部分を除去し、次に3N HClの添加によってpHを3に調節して、固体を得た。固体を濾過によって収集し、真空乾燥して、表題化合物(4.3g、51.76%)を得た。
2−(4−ブロモフェニル)酢酸エチル(30g、0.123mol)およびNMP(200mL)を合わせた。次にCuCN(33g、0.370mol)を小分けして添加し、次に脱気して、窒素を3回再充填した。次にCuI(4.7g、0.0247mol)を一度に添加した。反応物を脱気して、窒素を3回再充填し、次に160℃で4時間加熱した。次に反応物を180℃でさらに3時間加熱した。次に溶液を室温に冷却し、EtOAc(500mL)および水(500mL)で希釈した。10分間の撹拌後、反応物を濾過し、水層をEtOAc(500mL×2)で抽出した。合わせた有機層を鹹水で洗浄し、Na2SO4上で乾燥させ、乾燥するまで濃縮して、表題化合物(31g、66.5%)を褐色固体として得た。
6塩化−クロロニコチノイル(1.76g、10.00mmol)およびDCM(20mL)を合わせて氷浴内で冷却し、次にトリエチルアミン(2.09mL、15.0mmol)およびフェニルメタンアミン(1.072g、10.00mmol)を添加した。次に反応物を室温で3時間撹拌してから、DCM(30ml)中で希釈し、1N水性HCl(50ml)、飽和水性炭酸水素ナトリウム(50ml)、鹹水(50ml)で洗浄し、Na2SO4上で乾燥させて濃縮し、表題化合物(2.19g、89%)を淡いベージュ固体として得て、それをさらに精製せずに使用した。MSm/z[M+H]+247.1.
ヒドラジン(1.67mL、53.3mmol)およびN−ベンジル−6−クロロニコチンアミド(2.19g、8.88mmol)溶液をエタノール(70mL)中で合わせて、100℃で一晩加熱した。次に反応混合物を冷却し、蒸発させて固体を得た。固体を濾過によって収集し、70mLの水で洗浄して、熱エタノールから再結晶化させて、表題化合物(1.32g、61%)を灰白色固体として得た。MSm/z[M+H]+243.2.
N1,N1,N2,N2−テトラメチルエタン−1,2−ジアミン(0.15mL、1.000mmol)、2−(ピリジン−2−イル)酢酸メチル(1g、6.62mmol)、およびN,N−ジメチルホルムアミドジメチルアセタール(3.9mL、29.1mmol)を合わせて、115℃で一晩加熱した。次に反応混合物を冷却して、12mLの飽和水性塩化アンモニウムおよび12mLのEtOAcの間で分配した。有機層を分離させ、Na2SO4上で乾燥させて濃縮し、表題化合物を暗色油として得て、それをさらに精製せずに次のステップでそのまま使用した。1H NMR(400MHz,DMSO−
d6)δppm2.73(s,1H),2.64(brs,6H),3.50(s,6H),7.16(dd,J=6.95,5.43Hz,1H),7.26(dt,J=7.83,1.01Hz,1H),7.54(s,1H),7.65(td,J=7.71,1.77Hz,1H),8.49(d,J=4.04Hz,1H).MSm/z[M+H]+207.1
2(4−シアノフェニル)酢酸エチル(513mg)およびN,N−ジメチルホルムアミドジメチルアセタール(323mg)を合わせて、80℃で一晩加熱した。反応混合物を蒸発させて残渣を得て、それをジエチルエーテル(20ml)に溶解し、水(10ml)、鹹水(10ml)で抽出して、Na2SO4で乾燥させ、蒸発させて、表題化合物(537mg)をベージュの固体として得た。1H NMR(400MHz,クロロフォルム−d)δppm1.20(t,J=7.07Hz,3H),2.62−2.77(m,6H),4.13(q,J=7.07Hz,2H),7.29(d,J=8.59Hz,2H),7.56(d,J=8.59Hz,2H).
N−ベンジル−6−ヒドラジニルニコチンアミド(126mg、0.520mmol)および2−(4−シアノフェニル)−3−(ジメチルアミノ)アクリル酸エチル(127mg、0.520mmol)をエタノール(10mL)中で合わせて、室温で一晩撹拌した。反応混合物を蒸発させて残渣を得て、それをDCM(100ml)に溶解し、飽和水性炭酸水素ナトリウム(50ml)で抽出して、Na2SO4によって乾燥させ、濃縮して残渣を得て、それをクロマトグラフィー(12gのSiO2、0〜10%のDCM−MeOH)によって精製し、表題化合物(90mg、39%)を油として得た。MSm/z[M+H]+442.4.
N−ベンジル−6−ヒドラジニルニコチンアミド(200mg、0.826mmol)、3−(ジメチルアミノ)−2−(ピリジン−2−イル)アクリル酸メチル(170mg、0.826mmol)、およびTFA(0.127mL、1.651mmol)をエタノール(3mL)中で合わせて、室温で一晩撹拌した。反応混合物をEtOAc(50mL)中で希釈し、飽和水性炭酸水素ナトリウム(20ml)、鹹水(20ml)で洗浄して、Na2SO4で乾燥させて濃縮し、表題化合物(244mg)をオレンジ色の固体として得て、さらに精製せずに使用した。MSm/z[M+H]+404.4.
3−オキソアゼチジン−1−カルボン酸tert−ブチル(500mg、2.92mmol)およびN−メチルシクロブタンアミン(0.373mL、3.50mmol)の溶液を塩化メチレン(15mL)中で合わせて、トリアセトキシホウ水素化ナトリウム(929mg、4.38mmol)を添加して、溶液を20℃で3時間撹拌した。溶液を真空濃縮して、白色固体を得た。固体を酢酸エチル(50mL)に取り込み、飽和炭酸水素ナトリウム(50mL)および鹹水で洗浄し、硫酸マグネシウムで乾燥させて、真空濃縮して残渣を得て、それを40gのシリカゲルカラム上で精製し、ヘキサン誘導体中の0〜70%酢酸エチルで溶出して、表題化合物(342mg、1.423mmol、48.7%)を無色明瞭な油として得た。1H NMR(400MHz,メタノール−d4)δppm1.43(s,9H)1.60−1.75(m,2H)1.85−2.04(m,4H
)2.07(s,3H)2.81−2.94(m,1H)3.27−3.30(m,1H)3.81−3.88(m,2H)3.88−3.97(m,2H);MS:241(M+H).
塩化メチレン(6mL)中の3−(シクロブチル(メチル)アミノ)アゼチジン−1−カルボン酸tert−ブチル(285mg、1.186mmol)溶液を合わせて、ジオキサン中の4MHCl(1.186mL、4.74mmol)を添加して、溶液を20℃で30時間撹拌した。溶液を真空濃縮し、ヘプタン/塩化メチレンから濃縮して、酸性塩酸塩としての表題化合物(191mg、0.896mmol、76%)を淡黄色固体として得て、それをさらに精製せずに使用した。
塩化メチレン(5mL)中の3−オキソアゼチジン−1−カルボン酸tert−ブチル(175mg、1.022mmol)およびN−メチルシクロプロパンアミン塩酸塩(121mg、1.124mmol)の溶液を合わせて、トリアセトキシホウ水素化ナトリウム(325mg、1.533mmol)を添加して、溶液を20℃で30分間撹拌した。溶液を真空濃縮して白色固体を得て、それを酢酸エチル(50mL)に取り込み、飽和炭酸水素ナトリウム(50mL)および鹹水で洗浄し、硫酸マグネシウムで乾燥させて真空濃縮し、次に40gのシリカゲルカラム上で精製して、ヘキサン誘導体中の0〜50%酢酸エチルで溶出して、表題化合物(128mg、0.566mmol、55.3%)を無色透明な油として得た。MS:227(M+H).1H NMR(400MHz,メタノール−d4)δppm0.41−0.47(m,2H)0.48−0.56(m,2H)1.43(s,9H)1.64(tt,J=6.7,3.9Hz,1H)2.28(s,3H)3.50(tt,J=7.5,5.7Hz,1H)3.84−4.01(m,4H).
塩化メチレン(3mL)中の3−(シクロプロピル(メチル)アミノ)アゼチジン−1−カルボン酸tert−ブチル(73mg、0.323mmol)溶液、およびジオキサン中の4MHCl(0.323mL、1.290mmol)を合わせて、溶液を20℃で4時間撹拌し、次にジオキサン中の4MHCl(0.323mL、1.290mmol)を添加して、20℃で21時間撹拌した。次に溶液を真空濃縮して、塩酸塩としての表題化合物を得て、それをさらに精製せずに使用した。
6,6−ジフルオロ−1,4−ジアゼパン−1−カルボン酸tert−ブチル(49mg、0.207mmol)およびシアノ水素化ホウ素ナトリウム(52mg、0.83mmol)をTHF(1.5mL)中で合わせて、37%水性ホルムアルデヒド(0.077mL、1.037mmol)および酢酸(0.018mL、0.311mmol)を添加して、次に20℃で16時間撹拌した。次にメタノール(300uL)を添加して、混合物を真空濃縮して残渣を得て、それを酢酸エチル(40mL)に取り込み、飽和水性炭酸水素ナトリウム(50mL)および鹹水で洗浄し、硫酸マグネシウムで乾燥させて、真空濃縮して表題化合物(51mg、0.204mmol、98%)を無色透明な油として得た。MS:251(M+H).1H NMR(400MHz,クロロフォルム−d)δppm1.46(s,9H)2.50(s,3H)2.73(d,J=4.8Hz,2H)2.92(t,J=13.5Hz,2H)3.55(d,J=4.8Hz,2H)3.75−3.94(m,2H).
ジクロロメタン(2mL)中の6,6−ジフルオロ−4−メチル−1,4−ジアゼパン−1−カルボン酸tert−ブチル(50mg、0.200mmol)溶液、およびジオキサン中の4MHCl(0.4mL、1.6mmol)を合わせて、溶液を20℃で21時間撹拌した。次に反応物を真空濃縮して、酸性塩酸塩としての表題化合物を得て、それをさらに精製せずに使用した。MS:151(M+H).
4−ブロモ−2−フルオロ−5−メチルベンゾニトリル(4g、18.69mmol)およびマロン酸ジメチル(29.9mL、262mmol)を合わせた。混合物を窒素でパージしながら、炭酸カリウム(3.87g、28.0mmol)、カリウム炭酸水素(2.81g、28.0mmol)、トリ−tert−ブチルホスホニウムテトラフルオロホウ酸塩(0.119g、0.411mmol)、およびビス(ジベンジルイジンアセトン)パラジウム(0)(0.118g、0.206mmol)を添加した。反応混合物を油浴内で170℃で3時間加熱して、次に冷却し、酢酸エチルで希釈して、セライト(登録商標)を通して濾過した。濾液を濃縮して、残渣をEtOAcに溶解し、1M水酸化ナトリウム水溶液(2×)、10%水性塩化ナトリウムで2回、および鹹水で抽出した。有機相を硫酸ナトリウム上で乾燥させ、濾過して、真空濃縮し、次にフラッシュクロマトグラフィーによって精製し、表題化合物(1.67g、43%)を無色透明な油として得た。1H NMR(400MHz,クロロフォルム−d)δppm2.30(s,3H)3.67(s,2H)3.72(s,3H)7.10(d,J=9.60Hz,1H)7.42(d,J=6.32Hz,1H).
4−ブロモ−2−フルオロ−3−メチルベンゾニトリル(2g、9.34mmol)、マロン酸ジメチル(12.28mL、107mmol)、炭酸カリウム(1.937g、14.02mmol)、および炭酸水素カリウム(1.403g、14.02mmol)を合わせた。この混合物に窒素ガスを激しく1分間吹き込み、次にトリ−tert−ブチルホスホニウムテトラフルオロホウ酸塩(0.030g、0.103mmol)、およびビス(ジベンジルイジンアセトン)パラジウム(0)(0.027g、0.047mmol)を添加した。次に反応混合物を油浴(170℃)内で加熱して、1時間撹拌し、次に周囲温度に冷却して、EtOAc(80mL)で希釈した。EtOAc層をデカントして、セライト(登録商標)(約7cm幅で1.5cm厚)プラグを通過させた。フラスコ内に残った大きな暗色沈殿物を追加量のEtOAcで希釈し、微細懸濁液が生じるまで超音波分解した。EtOAc粉砕物もまた、セライト(登録商標)プラグに通過させた。濾過からの有機物を合わせて約40℃、次に90℃で、45分間真空濃縮して残渣を得た。フラッシュカラムクロマトグラフィーを使用して残渣を精製し、表題化合物(1.05g、5.07mmol、54.2%)を無色透明な油として得た。1H NMR(400MHz,クロロフォルム−d)δppm2.17(d,J=2.27Hz,3H)3.63(s,3H)3.91(s,2H)7.29(d,J=8.08Hz,1H)7.71(t,J=7.33Hz,1H)
2−(4−シアノ−5−フルオロ−2−メチルフェニル)酢酸メチル(5.00g、24.13mmol)、1,1−ジメトキシ−N,N−ジメチルメタンアミン(32.2mL、241mmol)、および塩化リチウム(0.102g、2.413mmol)を合わせて、105℃で加熱した。2時間後、反応混合物を真空濃縮して、EtOAc(30mL)で繰り返し希釈し、濃縮して油を得た。油をEtOAc(50mL)に溶解し、水
、10%水性塩化ナトリウム、次に鹹水で洗浄した。有機層を硫酸ナトリウム上で乾燥させ、濾過して濃縮し、濃厚な赤色の油を得て、それを結晶化して、表題化合物を黄色固体として得た(6.1g、23.26mmol、96%)。1H NMR(400MHz,DMSO−d6)δppm2.10(s,3H)2.34(s,1H)2.54−2.81(m,6H)3.50(s,3H)7.20(d,J=10.11Hz,1H)7.58(s,1H)7.72(d,J=7.07Hz,1H).ESI−MSm/z[M+H]+263.2.
6−ヒドラジニルニコチン酸(1.10g、7.18mmol)、2−(4−シアノ−3−フルオロ−2−メチルフェニル)−3−(ジメチルアミノ)アクリル酸メチル(2.072g、7.90mmol)、2−プロパノール(18mL)、および0.5M水性塩酸(17.24mL、8.62mmol)を合わせた。2時間後、N−エチル−N−イソプロピルプロパン−2−アミン(6.26mL、35.9mmol)を添加した。さらに1時間後、反応混合物を水で希釈して、IPAcで2回洗浄した。水相をおよそpH=3.5に酸性化し、30分間撹拌して固体を得て、それを濾過によって収集し、水、エタノール、およびヘプタンで洗浄し、一晩真空乾燥して表題化合物を得た(1.60g、66%)。1H NMR(400MHz,DMSO−d6)δppm2.34(d,J=2.27Hz,3H)7.64(d,J=8.08Hz,1H)7.69−7.80(m,1H)8.26(br.s.,1H)8.48(br.s.,2H)8.98(t,J=1.52Hz,1H)13.45(br.s.,2H).ESI−MSm/z[M+H]+339.2.
6−ヒドラジニルニコチン酸(0.73g、4.77mmol)、2−(4−シアノ−5−フルオロ−2−メチルフェニル)−3−(ジメチルアミノ)アクリル酸メチル(1.375g、5.24mmol)、2−プロパノール(18mL)、および0.5M水性塩酸(11.44mL、5.72mmol)を合わせた。2時間後、N−エチル−N−イソプロピルプロパン−2−アミン(4.15mL、23.83mmol)。1時間後、反応混合物を水で希釈して、IPAcで2回洗浄した。水相をおよそpH=3.5に酸性化し、30分間撹拌して固体を得て、それを濾過によって収集し、水、エタノール、およびヘプタンで洗浄し、一晩真空乾燥して表題化合物を得た(1.20g、74%)。1H NMR(400MHz,DMSO−d6)δppm2.41(s,3H)7.74(d,J=7.07Hz,1H)7.91(d,J=11.62Hz,1H)8.26(s,1H)8.37−8.47(m,1H)8.47−8.56(m,1H)8.96(dd,J=2.15,0.88Hz,1H).ESI−MSm/z[M+H]+339.2.
4−ブロモ−2−フルオロ−5−メチルベンゾニトリル(4g、18.69mmol)およびマロン酸ジメチル(29.9mL、262mmol)を合わせて窒素でパージした。炭酸カリウム(3.87g、28.0mmol)、炭酸水素カリウム(2.81g、28.0mmol)、トリ−tert−ブチルホスホニウムテトラフルオロホウ酸塩(0.119g、0.411mmol)、およびビス(ジベンジルイジンアセトン)パラジウム(0)(0.118g、0.206mmol)を添加した。次に反応混合物を油浴内で170℃に加熱した。3時間後、反応混合物を冷却し、酢酸エチルで希釈して、セライト(登録商標)を通して濾過した。濾液を濃縮して、残渣をEtOAcに溶解した。有機溶液を1N水酸化ナトリウム水溶液(2×)、10%水性塩化ナトリウムで2回、次に鹹水で洗浄した。有機相を硫酸ナトリウム上で乾燥させ、濾過して真空濃縮し、残渣を得て、そ
れをフラッシュクロマトグラフィーによって精製し、表題化合物(1.67g、43%)を無色透明な油として得た。1H NMR(400MHz,クロロフォルム−d)δppm2.30(s,3H)3.67(s,2H)3.72(s,3H)7.10(d,J=9.60Hz,1H)7.42(d,J=6.32Hz,1H).
4−ブロモ−2−フルオロ−3−メチルベンゾニトリル(2g、9.34mmol)、マロン酸ジメチル(12.28mL、107mmol)、炭酸カリウム(1.937g、14.02mmol)、および炭酸水素カリウム(1.403g、14.02mmol)を合わせた。窒素で1分間パージして、次にトリ−tert−ブチルホスホニウムテトラフルオロホウ酸塩(0.030g、0.103mmol)、およびビス(ジベンジルイジンアセトン)パラジウム(0)(0.027g、0.047mmol)を添加した。反応物を予熱された油浴(170℃)内に入れた。1時間後、混合物を周囲温度に冷却し、EtOAc(80mL)で希釈した。EtOAc層をデカントして、セライト(登録商標)(約7cm幅で1.5cm厚)プラグを通過させた。フラスコ内に残った大きな暗色沈殿物を追加量のEtOAcで希釈し、微細懸濁液が生じるまで超音波分解した。EtOAc粉砕物もまたセライト(登録商標)プラグに通過させ、次に約40℃、次に90℃で45分間真空濃縮して、残渣を得て、それをフラッシュカラムクロマトグラフィーを使用して精製し、表題化合物(1.05g、5.07mmol、54.2%)を無色透明な油として得た。1H NMR(400MHz,クロロフォルム−d)δppm2.17(d,J=2.27Hz,3H)3.63(s,3H)3.91(s,2H)7.29(d,J=8.08Hz,1H)7.71(t,J=7.33Hz,1H).
2−(4−シアノ−3−フルオロ−2−メチルフェニル)酢酸メチル(10.0g、48.3mmol)、1,1−ジメトキシ−N,N−ジメチルメタンアミン(17.25g、145mmol)、および固体塩化リチウム(0.205g、4.83mmol)を合わせて、105℃で1.5時間加熱した。混合物を10℃に冷却して、水(210mL)を緩慢に添加した。固体を真空濾過によって収集し、DCM中に溶解して、カラムクロマトグラフィーによって精製し、表題化合物(7.95g、63%)を淡黄色固体として得た。1H NMR(400MHz,DMSO−d6)δppm2.07(d,J=2.53Hz,3H)2.54−2.86(m,6H)3.50(s,3H)7.10(d,J=7.83Hz,1H)7.62(s,1H)7.63−7.66(m,1H).ESI−MSm/z[M+H]+263.2.
マイクロ波管内で、Pd2(dba)3(0.070g、0.077mmol)およびトリシクロヘキシルホスフィン(0.103g、0.367mmol)を合わせた。ジオキサン(15.32ml)を添加して、得られた混合物を室温で30分間撹拌した。ビス(ピナコラト)二ホウ素(1.425g、5.61mmol)、酢酸カリウム(0.751g、7.65mmol)、および4−ブロモ−2−メチルベンゾニトリル(1g、5.10mmol)を連続的に添加した。管を窒素でフラッシュした。次に反応混合物を電子レンジ内で100℃で1時間撹拌した。混合物を水(26mL)で処理して、エーテルで抽出した。有機層を鹹水で洗浄し、硫酸ナトリウム上で乾燥させて濃縮し、表題化合物(1.55g)を得て、それをさらに精製せずに次のステップで使用した。
チンアミド
で調製された。1H NMR(400MHz,DMSO−d6)δppm1.11(t,J=6.95Hz,3H)1.69−1.84(m,2H)3.31−3.37(m,3H)3.40−3.45(m,3H)3.85(s,3H)7.33−7.56(m,2H)8.05(d,J=5.56Hz,1H)8.27−8.80(m,4H)8.84−8.98(m,1H)13.54(br.s.,1H).MSm/z[M+H]+398.3.
.30−1.41(m,6H)3.29(s,3H)3.48−3.61(m,2H)3.78−3.93(m,3H)7.36−7.44(m,1H)7.46−7.53(m,1H)7.95(s,1H)8.05(d,J=5.56Hz,1H)8.30−8.68(m,3H)8.84(d,J=1.52Hz,1H)13.53(br.s.,1H).MSm/z[M+H]+398.3.
コチンアミド
して、実施例1と同様の方法で調製された。1H NMR(400MHz,DMSO−d6)δppm1.52−1.73(m,1H)1.85−2.06(m,1H)3.37−3.82(m,7H)3.86(s,3H)3.93−4.03(m,1H)4.78(br.s.,1H)7.08−7.70(m,2H)8.06(d,J=5.05Hz,1H)8.18−8.85(m,4H)8.91(dt,J=5.56,1.39Hz,1H)13.53(br.s.,1H).MSm/z[M+H]+426.
の方法で調製された。1H NMR(400MHz,DMSO−d6)δppm1.75−1.93(m,2H)2.59(t,J=5.43Hz,3H)2.90−3.01(m,2H)3.37(q,J=6.57Hz,2H)3.88(s,3H)7.38−7.60(m,2H)8.07(d,J=5.56Hz,1H)8.21−8.79(m,5H)8.85(t,J=5.68Hz,1H)8.89−8.99(m,1H).MSm/z[M+H]+383.2.
36(m,7H)3.92(s,3H)7.53(s,1H)7.60(d,J=5.81Hz,1H)8.09(d,J=5.81Hz,1H)8.36−8.52(m,2H)8.61−8.74(m,2H)8.86−8.93(m,1H).MSm/z[M+H]+398.2.
NMR(400MHz,DMSO−d6)δppm0.20−0.74(m,4H)3.26(s,2H)3.32−3.38(m,2H)7.79(d,J=8.59Hz,2H)8.14(d,J=5.31Hz,2H)8.26−8.85(m,4H)8.86−8.98(m,1H)13.53(br.s.,1H).MSm/z[M+H]+404.1.
(m,3H)3.14−3.33(m,4H)3.77(dd,J=11.12,3.28Hz,2H)7.55−7.79(m,3H)7.99−8.72(m,4H)8.80−8.90(m,1H)13.14(br.s.,1H).MSm/z[M+H]+432.2.
ミド
ニコチン酸(50mg、0.163mmol)、EDC(46.9mg、0.245mmol)およびHOBT(37.5mg、0.245mmol)およびDMA(1mL)を合わせて、ヒューニッヒ塩基(0.114ml、0.653mmol)で処理し、周囲温度で5分間撹拌して、次に4−アミノ−1−Boc−ピペリジン(38.5mg、0.327mmol)を添加して、室温で一晩撹拌した。次に反応混合物をメタノールで約1.5mLの総容積に希釈して、分取HPLCを通じて精製した。生成物含有画分を収集して真空濃縮し、残渣を得て、それをDCM(2mL)中のTFA(2mL)で処理した。周囲温度で一晩の撹拌後、反応物を真空濃縮して真空乾燥し、表題化合物(39.3mg、62%)を黄色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.65−1.82(m,2H)1.93−2.08(m,2H)2.94−3.16(m,2H)3.35(d,J=12.63Hz,2H)3.99−4.19(m,1H)7.80(d,J=8.59Hz,2H)8.15(d,J=7.33Hz,2H)8.29−8.78(m,6H)8.87−8.99(m,1H)13.59(br.s.,1H).MSm/z[M+H]+389.2.
表題化合物(16.2mg、44%)を得た。1H NMR(400MHz,DMSO−d6)δppm0.93(t,J=7.33Hz,3H)1.67(五重項,J=7.20Hz,2H)2.70−2.95(m,2H)4.05−4.22(m,1H)7.80(d,J=8.34Hz,2H)8.15(br.s.,2H)8.41−8.86(m,4H)8.94(s,1H).MSm/z[M+H]+387.2.
)13.19−13.81(m,1H).MSm/z[M+H]+456.1.
,J=6.32Hz,1H)8.92(s,1H).MSm/z[M+H]+376.1.
NMR(400MHz,DMSO−d6)δppm1.60−1.83(m,2H)1.83−2.08(m,2H)2.18(dd,J=12.88,4.29Hz,1H)2.27−2.41(m,1H)2.44(s,3H)2.84(d,J=3.54Hz,3H)3.08(br.s.,1H)3.29(br.s.,1H)3.40(q,J=6.57Hz,2H)3.58(d,J=4.29Hz,1H)7.67(d,J=7.58Hz,1H)7.70−7.89(m,2H)8.20(br.s.,1H)8.42(br.s.,1H)8.50−8.71(m,1H)8.84(br.s.,1H)8.89−8.95(m,1H)9.53(br.s.,1H)12.81−13.56(m,1H).MSm/z[M+H]+431.2.
)8.40(d,J=6.06Hz,2H)8.60(br.s.,1H)8.77(d,J=7.07Hz,1H)8.83−8.95(m,1H)9.96(br.s.,1H)13.07−13.88(m,1H).MSm/z[M+H]+431.2.
NMR(400MHz,DMSO−d6)δppm3.11−4.08(m,8H)7.80(d,J=8.59Hz,2H)8.10(dd,J=8.59,2.02Hz,1H)8.15(d,J=7.83Hz,2H)8.46(br.s.,1H)8.54−8.59(m,1H)8.65(br.s.,1H)13.51(br.s.,1H).MSm/z[M+H]+376.1
m1.20(d,J=6.57Hz,6H)2.44(s,3H)4.13(dd,J=14.15,6.57Hz,1H)7.66(dd,J=8.08,1.52Hz,1H)7.74(s,1H)7.75−7.85(m,1H)8.07−8.28(m,1H)8.45(dd,J=19.70,6.82Hz,3H)8.84−8.98(m,1H)12.97−13.37(m,1H).MSm/z[M+H]+362.2.
−1−イル)−N−((1−(メトキシメチル)シクロペンチル)メチル)ニコチンアミド
1mg、0.427mmol)で処理した。得られた透明な混合物を一晩(15時間)撹拌して、次にヒューニッヒ塩基(297μl、1.708mmol)を添加して、反応物を周囲温度で2.5時間撹拌した。次に反応混合物を真空濃縮して、HPLC(水中の20〜95%ACN、TFA緩衝)を使用して精製した。生成物含有画分を真空濃縮して、固体(体積約20mL)を得た。固体を濾過し、真空乾燥して、表題化合物(57.4mg、34.2%の収率)を灰白色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.22(qd,J=12.21,4.29Hz,2H)1.62(d,J=12.88Hz,2H)1.81(m,J=10.96,7.29,3.76,3.76Hz,1H)3.20(t,2H)3.27(t,J=10.86Hz,2H)3.86(dd,J=11.24,2.65Hz,2H)8.29(s,1H)8.42(br.s.,3H)8.74(t,J=5.68Hz,1H)8.93(s,2H)13.41(br.s.,1H).MSm/z[M+H]+394.
して、熱MeOH(3〜6mL)から再結晶化させ、表題化合物(79.2mg、67.5%の収率)を白色固体として得た。MSm/z[M+H]+360.
4(m,3H)1.65−1.94(m,4H)2.41(s,3H)3.66−3.82(m,1H)7.27(br.s.,2H)7.43(d,J=8.34Hz,1H)7.46−7.50(m,1H)7.77(s,1H)8.14−8.34(m,3H)8.54(d,J=8.84Hz,1H)8.81(d,J=2.02Hz,1H).MSm/z[M+H]+416.2.
8.43(br.s.,2H)8.72(br.s.,1H)8.92(s,1H).MSm/z[M+H]+434.4.
LのDMSOで希釈して、分取HPLC(ACN/水、ギ酸添加)によって精製し、表題化合物(25mg、39.5%の収率)を黄色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.72−1.95(m,2H)2.10−2.21(m,2H)2.21−2.35(m,2H)3.31(s,3H)3.65(s,2H)7.79(d,J=8.6Hz,2H)8.14(d,J=6.1Hz,2H)8.44(d,J=6.6Hz,2H)8.65(s,2H)8.87−8.95(m,1H)13.55(br.s.,1H).MSm/z404[M+H]+.
NMR(400MHz,DMSO−d6)δppm1.13−1.27(m,1H)1.38−1.50(m,3H)1.60(d,J=12.9Hz,1H)1.62−1.70(m,2H)1.71−1.82(m,1H)2.44(s,3H)3.26−3.33(m,2H)3.35−3.45(m,2H)3.87(dd,J=11.0,1.9Hz,1H)7.66(dd,J=8.0,1.4Hz,1H)7.72(s,1H)7.80(d,J=8.1Hz,1H)8.16(s,1H)8.40(br.s.,2H)8.67(t,J=5.6Hz,1H)8.90(t,J=1.5Hz,1H)13.18(br.s.,1H).MSm/z432[M+H]+.
+H]+.
継続した。反応混合物をEtOAcで希釈して、セライト(登録商標)上で濃縮し、10gのNHシリカゲルカラム上で精製して、ヘキサン誘導体中の10〜100%EtOAcで溶出して、6−(4−(2−(ジメチルアミノ)ピリジン−4−イル)−5−メトキシ−1H−ピラゾール−1−イル)−N−((テトラヒドロ−2H−ピラン−4−イル)メチル)ニコチンアミドを褐色油として得た。MSm/z437[M+H]+.
,J=11.6,1.5Hz,1H)8.29(br.s.,1H)8.39−8.46(m,1H)8.48(br.s.,1H)8.60(br.s.,1H)8.73(t,J=5.4Hz,1H)8.89−8.96(m,1H)13.77(br.s.,1H).MSm/z396[M+H]+.
−(3−メトキシプロピル)ニコチンアミドおよび(2−エトキシピリジン−4−イル)ボロン酸を使用して、実施例213と同様の方法で調製された。1H NMR(400MHz,DMSO−d6)δppm1.25(t,J=7.1Hz,3H)1.71(五重項,J=6.7Hz,2H)3.18(s,3H)3.21−3.29(m,2H)3.32(t,J=6.3Hz,2H)4.22(q,J=7.1Hz,2H)7.31(s,1H)7.40(d,J=5.3Hz,1H)7.94(d,J=5.6Hz,1H)8.26−8.34(m,1H)8.34−8.42(m,1H)8.47(br.s.,1H)8.61(t,J=5.6Hz,1H)8.82(d,J=1.5Hz,1H)13.42(br.s.,1H).MSm/z398[M+H]+.
H−ピラゾール−1−イル)−N−(3−メトキシプロピル)ニコチンアミド
H−ピラゾール−1−イル)ニコチン酸および1−(テトラヒドロ−2H−ピラン−4−イル)シクロプロパンアミンを使用して、実施例227と同様の方法で調製された。1H
NMR(400MHz,DMSO−d6)δppm0.82−1.03(m,5H)1.25(s,1H)1.45−1.67(m,3H)1.74(d,J=12.4Hz,2H)3.37(t,J=11.6Hz,2H)4.03(dd,J=11.4,3.5Hz,2H)4.09(s,3H)7.22(s,1H)7.31(d,J=6.1Hz,1H)7.41(s,1H)7.83(d,J8.6Hz,1H)7.90(s,1H)8.13(d,J=6.1Hz,1H)8.37(dd,J=8.7,2.1Hz,1H)8.83(d,J=1.8Hz,1H).MSm/z[M+H]+436.4.
r.s.,3H)7.28(br.s.,2H)8.14(s,1H)8.20(br.s.,1H)8.26(d,J=2.3Hz,1H)8.56(t,J=5.4Hz,2H)8.80(d,J=6.3Hz,1H)8.86(br.s.,1H)12.97(br.s.,1H).MSm/z[M+H]+422.4.
8.36(br.s.,1H)8.70(br.s.,1H)8.82−8.88(m,1H)13.16(br.s.,1H).MSm/z[M+H]+452.5.
−ピラゾール−1−イル)−N−(2−(トリフルオロメトキシ)エチル)ニコチンアミド
75mm)によって精製して、水(0.1%水酸化アンモニウム添加)中のACN(0.1%水酸化アンモニウム添加)で溶出して、表題化合物(7.3mg、26.0%)を得た。1H NMR(400MHz,DMSO−d6)δ1.05−1.23(m,2H)1.49−1.58(m,2H)1.74(ttt,J=11.1,11.1,7.3,7.3,3.7,3.7Hz,1H)2.01(s,1H)3.08−3.13(m,3H)3.63(s,3H)3.77(d,J=2.8Hz,1H)3.80(s,4H)7.07(br.s.,1H)7.63(d,J=5.3Hz,1H)8.04−8.09(m,2H)8.19(dd,J=8.8,2.3Hz,1H)8.45(d,J=8.8Hz,1H)8.53(t,J=5.8Hz,1H)8.78(d,J=2.0Hz,1H).MSm/z[M+H]+440.5.
8.46−8.39(m,2H),8.13(d,J=8.0Hz,2H),7.78(d,J=8.0Hz,2H),3.44−3.41(m,2H),2.70−2.67(m,2H),2.44−2.38(m,3H).MSm/Z[M+H]+410.1.
l)、およびEt3N(198mg、1.96mmol)をDMF(3.0mL)中で合わせた。混合物を室温で0.5時間撹拌し、次にtert−ブチル(3−アミノプロピル)(メチル)カルバメート(147.39mg、0.79mmol)を添加した。混合物を室温で一晩撹拌した。反応混合物を分取HPLCによって精製して、tert−ブチル(3−(6−(4−(4−シアノフェニル)−5−ヒドロキシ−1H−ピラゾール−1−イル)ニコチンアミド)プロピル)(メチル)カルバメート(150mg、48%)を得た。
ボニル)ピリジン−2−イル)−1H−ピラゾール−4−イル)−3−メチルベンゾニトリル
ppm1.34−1.48(m,2H)1.49−1.65(m,4H)1.76−1.88(m,2H)3.17(s,3H)3.31(br.s.,1H)3.73−3.87(m,1H)7.62(dd,J=8.2,1.6Hz,1H)7.77(dd,J=11.7,1.6Hz,1H)8.16(d,J=3.0Hz,1H)8.31−8.44(m,3H)8.55(t,J=8.0Hz,1H)8.84(dd,J=2.0,1.0Hz,1H)13.71(br.s.,1H).
イル)−3−メチルベンゾニトリル
,DMSO−d6)δppm0.60−0.75(m,2H)0.83−0.95(m,2H)1.72(五重項,J=6.69Hz,2H)2.10(d,J=5.05Hz,1H)3.18(s,3H)3.22−3.36(m,4H)7.41(d,J=1.26Hz,1H)7.57(dd,J=8.08,1.77Hz,1H)7.63−8.55(m,4H)8.64(br.s.,1H)8.77−8.90(m,1H);ESI−MSm/z[M+H]+418.4.
.48(m,5H)2.87−3.00(m,2H)3.18(q,J=10.11Hz,2H)3.71−3.89(m,1H)7.59−7.81(m,3H)8.15(br.s.,1H)8.23−8.53(m,3H)8.82−8.96(m,1H)13.14(br.s.,1H).ESI−MSm/z[M+H]+485.2.
ミンを使用して、実施例303と同様の方法で調製された。1H NMR(400MHz,DMSO−d6)δppm1.39(d,J=9.60Hz,1H)1.66(d,J=13.89Hz,3H)1.82(br.s.,2H)2.01(br.s.,2H)2.83−3.13(m,7H)3.32−3.58(m,4H)7.79(d,J=8.34Hz,2H)8.13(br.s.,3H)8.58(br.s.,3H)9.05−9.50(m,1H)12.43−14.49(m,1H).ESI−MSm/z[M+H]+445.2.
化リチウム(66.2mg、1.561mmol)を添加して、70℃で一晩加熱した。次に粗製反応物をDMSO(500uL)で希釈して、分取HPLC(アセトニトリル−水、TFA添加)を通じて精製し、表題化合物(24.6mg、0.057mmol、36.3%)を白色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.23(t,J=7.33Hz,3H)2.33(d,J=2.27Hz,3H)3.16(t,J=7.20Hz,2H)3.24−4.06(m,8H)7.49−7.84(m,2H)8.04−8.30(m,2H)8.43(br.s.,1H)8.60(dd,J=2.15,0.63Hz,1H).ESI−MSm/z[M+H]+435.3.
d6)δppm2.42(s,3H)2.59−2.74(m,4H)3.25(q,J=10.11Hz,2H)3.39−3.71(m,4H)7.65(dd,J=8.08,1.52Hz,1H)7.72(s,1H)7.78(d,J=8.08Hz,1H)8.06(dd,J=8.72,2.15Hz,1H)8.15(s,1H)8.39(d,J=8.34Hz,1H)8.53(dd,J=2.27,0.76Hz,1H)12.45−13.65(m,1H).ESI−MSm/z[M+H]+471.2.
,1H)7.71−7.78(m,1H)7.91−8.81(m,4H).ESI−MSm/z[M+H]+421.3.
NMR(400MHz,DMSO−d6)δppm0.58−1.34(m,4H)2.33(d,J=2.27Hz,3H)2.91(s,3H)3.31−3.85(m,6H)7.62(d,J=7.83Hz,1H)7.70−7.78(m,1H)7.82−8.75(m,4H).ESI−MSm/z[M+H]+447.3.
R(400MHz,DMSO−d6)δppm1.66−1.93(m,2H)2.34(d,J=2.27Hz,3H)2.98(s,3H)3.07−3.67(m,7H)7.64(br.s.,1H)7.70−7.81(m,1H)7.84−8.64(m,4H).ESI−MSm/z[M+H]+424.3.
6.62(m,1H)7.63(d,J=7.33Hz,1H)7.74(t,J=7.58Hz,1H)8.08(d,J=8.34Hz,1H)8.13−8.51(m,2H)8.54(d,J=1.77Hz,1H).ESI−MSm/z[M+H]+499.3.
ヒドロキシ−1H−ピラゾール−1−イル)ニコチン酸および(R)−1,2−ジメチルピペラジンを使用して、実施例303と同様の方法で調製された。1H NMR(400MHz,DMSO−d6)δppm1.01−1.53(m,3H)2.33(d,J=2.27Hz,3H)2.84(br.s.,3H)2.93−4.70(m,7H)7.63(d,J=7.07Hz,1H)7.71−7.80(m,1H)7.88−8.77(m,4H).ESI−MSm/z[M+H]+435.3.
−ジアザスピロ[3.3]ヘプタン−2−カルボニル)ピリジン−2−イル)−1H−ピラゾール−4−イル)−5−メチルベンゾニトリル
2.
)8.07(d,J=6.82Hz,2H)8.35(d,J=8.08Hz,3H)8.56(br.s.,1H)8.74−8.93(m,1H)13.42(br.s.,1H);ESI−MSm/z[M+H]+392.2.
H−ピラゾール−1−イル)ニコチン酸およびN,1−ジメチルピロリジン−3−アミンを使用して、実施例74と同様の方法で調製され、TFA塩が得られた。1H NMR(400MHz,DMSO−d6)δppm2.09−2.32(m,2H)2.43(s,3H)2.76−2.94(m,3H)2.98(s,3H)3.13−3.45(m,2H)3.72(br.s.,2H)4.94(br.s.,1H)7.61−7.84(m,3H)8.01−8.26(m,2H)8.42(br.s.,1H)8.58(br.s.,1H);ESI−MSm/z[M+H]+417.2.
(br.s.,1H)3.46−3.75(m,1H)4.05(br.s.,1H)7.60(dd,J=7.96,1.64Hz,1H)7.66(d,J=1.26Hz,1H)7.90(d,J=8.34Hz,1H)8.01(dd,J=8.72,2.15Hz,1H)8.06(s,1H)8.43(d,J=8.59Hz,1H)8.51(d,J=1.77Hz,1H)11.83−12.92(m,1H);ESI−MSm/z[M+H]+431.3.
;ESI−MSm/z[M+H]+417.3.
H−ピラゾール−1−イル)ニコチン酸および(R)−N−シクロプロピル−N−メチルピペリジン−3−アミン二塩酸塩を使用して、実施例112と同様の方法で調製された。1H NMR(400MHz,DMSO−d6)δppm0.13−0.61(m,4H)1.38−1.64(m,2H)1.64−2.09(m,3H)2.15−2.41(m,3H)2.43(s,3H)2.55−2.86(m,2H)3.04(br.s.,1H)3.49−3.87(m,1H)4.33−4.77(m,1H)7.65(dd,J=8.08,1.52Hz,1H)7.72(s,1H)7.81(d,J=8.08Hz,1H)8.05(dd,J=8.59,2.02Hz,1H)8.13(s,1H)8.40(d,J=7.33Hz,1H)8.53(d,J=1.77Hz,1H);ESI−MSm/z[M+H]+457.3.
2.43(s,3H)3.09(br.s.,1H)3.23(d,J=9.09Hz,1H)3.41(br.s.,3H)3.67−4.42(m,1H)4.42−5.15(m,1H)7.67(d,J=8.30Hz,1H)7.72−7.81(m,2H)8.10(d,J=8.08Hz,1H)8.19(br.s.,1H)8.33−8.62(m,2H)9.98(br.s.,1H)13.20(br.s.,1H);ESI−MSm/z[M+H]+417.3.
H)9.83(br.s.,1H);ESI−MSm/z[M+H]+457.3.
[2.5]オクタン−7−カルボニル)ピリジン−2−イル)−1H−ピラゾール−4−イル)−3−メチルベンゾニトリル
NMR(400MHz,DMSO−d6)δppm0.98−1.51(m,9H)2.43(s,3H)2.88−3.28(m,2H)3.28−3.66(m,2H)3.90(br.s.,2H)4.61(br.s.,1H)7.64−7.71(m,1H)7.71−7.82(m,2H)8.08−8.39(m,2H)8.63(s,2H)9.80(br.s.,1H);ESI−MSm/z[M+H]+445.3.
2(s,3H)2.85(br.s.,3H)3.21(br.s.,1H)3.34(br.s.,1H)3.40−3.74(m,2H)7.80(d,J=7.07Hz,1H)7.87(br.s.,1H)8.13(d,J=8.59Hz,1H)8.30(br.s.,1H)8.49(br.s.,1H)8.56−8.65(m,1H)9.85−10.51(m,1H);ESI−MSm/z[M+H]+421.3.
Hz,2H)2.43(s,3H)3.25(s,3H)3.38−3.41(m,4H)7.08(br.s.,2H)7.58(d,J=8.08Hz,1H)7.88(d,J=9.35Hz,1H)7.97(s,1H)8.29(dd,J=8.46,2.40Hz,1H)8.50(d,J=8.34Hz,1H)8.61(t,J=6.06Hz,1H)8.85(d,J=1.77Hz,1H);MS(M+H)+392.
1H NMR(400MHz,DMSO−d6)δppm1.74−1.82(m,2H)2.42(s,3H)3.25(s,3H)3.38−3.44(m,4H)6.54(br.s.,1H)7.79(d,J=7.07Hz,1H)7.89(br.s.,1H)8.28(br.s.,1H)8.41(d,J=6.32Hz,1H)8.71(t,J=5.68Hz,1H)8.91(s,1H)13.61(br.s.,1H);C21H20FN5O3について計算されたESI−MSm/z(M+H)+、410.16;実測値410.5.
合物を淡いピンク色の固体として得た。1H NMR(400MHz,DMSO−d6)δppm2.43(s,3H)2.79(s,3H)3.16(br.s.,4H)3.64−4.57(m,4H)7.67(d,J=7.83Hz,1H)7.74(s,1H)7.78(br.s.,1H)8.12(d,J=7.33Hz,1H)8.21(br.s.,1H)8.51(br.s.,1H)8.57−8.61(m,1H);C22H22N6O2について計算されたESI−MSm/z(M+H)+、403.18;実測値403.2.
8(d,J=6.82Hz,2H)2.85−3.14(m,2H)4.40(br.s.,2H)7.46−7.51(m,1H)7.54(s,1H)7.82−7.90(m,2H)8.14−8.16(m,1H)8.43(d,J=1.77Hz,1H)8.50(d,J=8.59Hz,1H);C25H28N6O2について計算されたESI−MSm/z(M+H)+、445.23;実測値445.5.
6O3について計算されたESI−MSm/z(M+H)+、473.22;実測値473.5.
いて計算されたESI−MSm/z(M+H)+、403.18;実測値403.3.
NMR(400MHz,DMSO−d6)δppm1.06(t,J=7.20Hz,3H)1.30(d,J=6.82Hz,3H)2.14−2.28(m,1H)2.31−2.45(m,4H)2.53−2.60(m,2H)2.81−3.06(m,2H)3.13−3.43(m,2H)4.08−4.62(m,1H)7.64(d,J=7.33Hz,1H)7.96(dd,J=8.84,2.27Hz,1H)8.08(s,1H)8.19(d,J=12.63Hz,1H)8.43−8.52(m,2H).ESI−MSm/z[M+H]+449.3、滞留時間:0.79分間。
:エタノール(1:1)に取り込み、溶液がほぼ完全に半透明になるまで、撹拌して還流させた。熱い溶液を濾過して、次に周囲温度に緩慢に冷却し、周囲温度で一晩緩慢に撹拌して、固体固体を濾過して、水:エタノール(1:1、2mL)で洗浄し、濾紙上で部分的に乾燥させ、次に収集して真空乾燥して、表題化合物(67.7mg、0.157mmol、50.4%の収率)を白色固体として得た。1H NMR(400MHz,DMSO−d6)δppm1.01(s,3H)1.21−1.37(m,3H)1.92−2.06(m,1H)2.09−2.21(m,1H)2.42(s,5H)2.67−2.99(m,2H)3.05−4.61(m,3H)7.61(dd,J=8.08,1.52Hz,1H)7.68(s,1H)7.86(d,J=8.08Hz,1H)8.00(dd,J=8.59,2.27Hz,1H)8.08(s,1H)8.40(d,J=8.59Hz,1H)8.49(d,J=2.27Hz,1H).ESI−MSm/z[M+H]+431.3、滞留時間:0.80分間。
択し得る。本発明の医薬組成物は、例えば、錠剤、カプセル、カシェ剤、紙、ロゼンジ、ウェファー、エリキシル剤、軟膏、経皮パッチ、煙霧剤、吸入剤、坐薬、溶液、および懸濁液の形態で、患者に投与してもよい。
血(HIVおよび肝炎などのための抗ウイルス投薬計画による処置)、慢性疾患の貧血、がん病状に伴う貧血、がん療法に起因する貧血、関節リウマチなどの慢性免疫障害の貧血、炎症性腸疾患、狼瘡、月経、鉄プロセッシング欠陥、急性または慢性腎臓病、感染症、炎症、照射、毒素、糖尿病;例えば、ウイルス、細菌、および/または寄生生物に起因する感染症;例えば、外傷、胃潰瘍、十二指腸潰瘍、痔疾、胃または大腸がん、傷害、外科手術に起因する失血などに伴い得る貧血;骨髄機能不全または骨髄機能低下に伴う疾患;小球性貧血、低色素性貧血、鉄芽球性貧血などを含むが、これに限定されるものではない。
量を判定できるであろう。
PHD2酵素(残基181〜417)のIC50値は、増大する量の阻害物質および固定量の酵素(5nM、最終濃度)およびビオチン標識ペプチド(ビオチン−Asp−Leu−Glu−Met−Leu−Ala−Pro−Tyr−Ile−Pro−Met−Asp−Asp−Asp−Phe−Gln−Leu、1uMの最終濃度)および2−オキシグルタル酸(2uM最終濃度)を50mM HEPES、50mM KCl、0.5mM TCEP、2uM FeCl2、0.1mg/mlのBSA、pH7.3中で混合することで判定される。阻害物質存在下で、室温で60分間酵素を前保温して、反応を実施した。ペプチド、2−オキソグルタル酸(最終濃度については上記参照)、およびアスコルビン酸(1mMの最終濃度)を添加することで、遊離酵素の活性を測定した。60分後に、過剰な強力結合阻害物質をアッセイ混合物に添加することで、酵素活性をクエンチした。放出された生成物の量をLC/を使用して測定した。放出された生成物の量をLC/MSシステム(Applied Biosystems API3000質量分光計付きAgilent HPLC)を使用して測定した。データは、IC50値の判定のための古典的等温式を使用して分析され、pIC50、すなわち−log(IC50)であり、式中、IC50はモル濃度であり、pIC50として報告され、すなわち−log(IC50)であり、式中、IC50はモル濃度である。
(二次アッセイ)を使用してPHD阻害を判定した
細胞ベースのHIF−α安定化アッセイ:
H9c2ラット心筋細胞(ATCC)を96ウェル組織培養マイクロプレート内に播種して、化合物(11点範囲の連続希釈)またはジメチルスルホキシドビヒクルの添加前に24時間培養した。24時間の化合物培養後、プロテアーゼおよびホスファターゼ阻害剤を含有する細胞抽出緩衝液(Meso−Scale Discovery)中で細胞を溶解することで、ホールセル抽出物を調製した。HIF1aタンパク質含有量をELISA(Meso−ScaleDiscovery)によって評価し、陽性対照デスフェリオキサミン(Sigma−Aldrich)から得られた最大応答の%として表した。化合物EC50をXL fit4 MicroSoft Excel曲線適合ソフトウェアを使用して、曲線適合によって得た。XLfit4を使用して、デスフェリオキサミン最大応答の50%をもたらす化合物濃度を計算して、化合物EC50posを得た。
PHD阻害剤またはビヒクルを8週齢オスC57マウスまたはSprague Dawleyラットに経口投与した。投薬4時間後、心臓を迅速に摘出し、定圧(80mmHg)のランゲンドルフ装置内で、修正Krebs−Henseleit緩衝液を用いて逆向性の様式で灌流した。梗塞サイズを測定するために、平衡に達するまで心臓を最初に20分間灌流し、次に30分間の広範囲の虚血(フローなし)に曝露して、マウスでは60分間の再灌流、またはラットでは90分間の再灌流期間がそれに続いた。心室を横に5つのセクションに切断した。切片を1%の2,3,5−トリフェニルテトラゾリウム塩化物(TTC)で染色し、スキャンして、梗塞面積および全面積を測定した。60分間の再灌流期間中に冠動脈流出物中に放出された乳酸デヒドロゲナーゼ(LDH)を測定することで、心臓の傷害を評価した(マウスのみ)。LDH活性試験キット(MBL International Corp.)を使用して、放出LDH量を測定し、ビヒクル処理心臓の%として表した。
PHD阻害剤またはビヒクルを4匹の群のオスC57BL/6に経口投与した。化合物は、30mg/kgおよび60mg/kgの用量で、50mMリン酸ナトリウムpH7.4中の30%ヒドロキシプロピルβ−シクロデキストリンに配合された。投薬の2時間後、マウスをCO2によって安楽死させ、心臓を迅速に摘出して2つに切断した。下方の(尖端)部分を急速凍結して−80℃で保存し、qRT−PCRを適用して、Life Technologies#4392938と、Qiagen#74881 RNeasy
96 Universal Tissue Kitを使用するRNA抽出物プロトコルとを使用して、VEGF遺伝子変化について分析した。対照は、100μg/mL濃度のビヒクル処理動物を合わせたRNAから作成され、7点曲線は、1:4希釈液および空試験から作成される。Applied BiosystemsからのStepOnePlusリアルタイムPCRシステムを使用して、RNA−to−Cт 1−ステップ法を使用
してサンプルをランし、相対的定量化は、VEGFの量を参照遺伝子の量で除して表される。処理群およびビヒクル対照を合わせて、平均化した。
Claims (8)
- 式5
R 3 は、それぞれ、水素、ヒドロキシル、アミノ、C 1〜8 アルキルアミノ、シアノ、ハロ、任意選択的に置換されたC 1〜6 アルキル、およびC 1〜4 アルコキシからなる群から独立して選択され;
R 4 は、水素、シアノ、ハロ、メチル、エチル、メトキシ、およびトリフルオロメチルからなる群から選択され;
R 5 は、
R 6 は、それぞれ、水素、シアノ、ハロ、C 3〜8 シクロアルキル、任意選択的に置換されたC 1〜6 アルキル、C 1〜4 アルコキシ、およびトリフルオロメチルからなる群から独立して選択され;
R 7 は、シアノおよびシアノメチルからなる群から選択され;
R 8 は、それぞれ、水素、シアノ、ハロ、C 1〜6 アルキル、C 1〜4 アルコキシおよびトリフルオロメチルからなる群から独立して選択される。)
の化合物、またはその薬学的に許容可能な塩。 - R5が
- 各R 6 がC 1〜6 アルキルである、請求項1に記載の化合物または薬学的に許容可能な塩。
- 各R8が水素である、請求項1に記載の化合物または薬学的に許容可能な塩。
- 各R3が水素であり、かつR4が水素である、請求項1に記載の化合物または薬学的に許容可能な塩。
- 4−(5−ヒドロキシ−1−(5−(モルホリン−4−カルボニル)ピリジン−2−イル)−1H−ピラゾール−4−イル)ベンゾニトリル;
2−フルオロ−4−(5−ヒドロキシ−1−(5−(モルホリン−4−カルボニル)ピリジン−2−イル)−1H−ピラゾール−4−イル)−3−メチルベンゾニトリル;
2−フルオロ−4−(5−ヒドロキシ−1−(5−(モルホリン−4−カルボニル)ピリジン−2−イル)−1H−ピラゾール−4−イル)−5−メチルベンゾニトリル;および
上述の化合物の何れか1つの薬学的に許容可能な塩からなる化合物群から選択される、請求項1に記載の化合物。 - 請求項1〜6のいずれか1項に記載の化合物または薬学的に許容可能な塩と、薬学的に許容可能な賦形剤とを含んでなる医薬組成物。
- 医薬として使用するための、請求項1〜6のいずれか一項に記載の化合物または薬学的に許容可能な塩。
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AU2014241183B2 (en) * | 2013-03-29 | 2018-08-09 | Takeda Pharmaceutical Company Limited | 6-(5-hydroxy-1H-pyrazol-1-yl)nicotinamide derivatives and their use as PHD inhibitors |
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