CN113166109A - 氨基吡啶类化合物及其制备方法和用途 - Google Patents
氨基吡啶类化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN113166109A CN113166109A CN201980071722.7A CN201980071722A CN113166109A CN 113166109 A CN113166109 A CN 113166109A CN 201980071722 A CN201980071722 A CN 201980071722A CN 113166109 A CN113166109 A CN 113166109A
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- Prior art keywords
- alkyl
- compound
- alkoxy
- hydrogen
- halogen
- Prior art date
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- -1 Aminopyridine compound Chemical class 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title abstract description 107
- 102000007471 Adenosine A2A receptor Human genes 0.000 claims abstract description 37
- 108010085277 Adenosine A2A receptor Proteins 0.000 claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 230000002265 prevention Effects 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 382
- 229910052739 hydrogen Inorganic materials 0.000 claims description 132
- 239000001257 hydrogen Substances 0.000 claims description 131
- 150000002431 hydrogen Chemical class 0.000 claims description 96
- 229910052736 halogen Inorganic materials 0.000 claims description 95
- 150000002367 halogens Chemical class 0.000 claims description 95
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 93
- 150000003839 salts Chemical class 0.000 claims description 71
- 239000000651 prodrug Substances 0.000 claims description 67
- 229940002612 prodrug Drugs 0.000 claims description 67
- 150000001204 N-oxides Chemical class 0.000 claims description 65
- 239000002207 metabolite Substances 0.000 claims description 65
- 239000012453 solvate Substances 0.000 claims description 63
- 125000001424 substituent group Chemical group 0.000 claims description 60
- 150000003254 radicals Chemical class 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 57
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 52
- 125000000623 heterocyclic group Chemical group 0.000 claims description 47
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 35
- 239000000460 chlorine Substances 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 29
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 28
- 239000011737 fluorine Substances 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 26
- 229910052794 bromium Inorganic materials 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 25
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 238000005859 coupling reaction Methods 0.000 claims description 24
- 125000001188 haloalkyl group Chemical group 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 23
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 23
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 15
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 14
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 13
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 238000001990 intravenous administration Methods 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 125000001425 triazolyl group Chemical group 0.000 claims description 10
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 9
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 claims description 8
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 229910017711 NHRa Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 238000001361 intraarterial administration Methods 0.000 claims description 3
- 238000007912 intraperitoneal administration Methods 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- 125000004306 triazinyl group Chemical group 0.000 claims description 3
- 238000007918 intramuscular administration Methods 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
- 238000006243 chemical reaction Methods 0.000 description 78
- 238000004949 mass spectrometry Methods 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
- 239000000243 solution Substances 0.000 description 40
- XVEPVTWPMLSUAV-UHFFFAOYSA-N 3-bromo-6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyridin-2-amine Chemical compound CC1=C2C=C(C=CC2=NC=N1)C3=CC(=C(N=C3C4=CC=C(C=C4)F)N)Br XVEPVTWPMLSUAV-UHFFFAOYSA-N 0.000 description 36
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
- 239000003960 organic solvent Substances 0.000 description 24
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- 235000011181 potassium carbonates Nutrition 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 16
- 239000003480 eluent Substances 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 229910052751 metal Inorganic materials 0.000 description 13
- 239000002184 metal Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
- 229910000024 caesium carbonate Inorganic materials 0.000 description 11
- 239000012046 mixed solvent 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
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229960005305 adenosine Drugs 0.000 description 10
- 230000003042 antagnostic effect Effects 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 229910052740 iodine Inorganic materials 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- FMQMMWXVYLBQED-UHFFFAOYSA-N 2-amino-6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyridine-3-carboxylic acid Chemical compound CC1=C2C=C(C=CC2=NC=N1)C3=CC(=C(N=C3C4=CC=C(C=C4)F)N)C(=O)O FMQMMWXVYLBQED-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- FJSOHKGATAJICX-UHFFFAOYSA-N 2-amino-6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyridine-3-carbonitrile Chemical compound CC1=C2C=C(C=CC2=NC=N1)C3=C(N=C(C(=C3)C#N)N)C4=CC=C(C=C4)F FJSOHKGATAJICX-UHFFFAOYSA-N 0.000 description 8
- BZQMAPAPQOGBIZ-UHFFFAOYSA-N 6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyridin-2-amine Chemical compound CC1=C2C=C(C=CC2=NC=N1)C3=C(N=C(C=C3)N)C4=CC=C(C=C4)F BZQMAPAPQOGBIZ-UHFFFAOYSA-N 0.000 description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
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- 229940124597 therapeutic agent Drugs 0.000 description 8
- UCNGGGYMLHAMJG-UHFFFAOYSA-N 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(C)C=C1B1OC(C)(C)C(C)(C)O1 UCNGGGYMLHAMJG-UHFFFAOYSA-N 0.000 description 7
- MXXFJWVAVZXIJN-UHFFFAOYSA-N 4-chloro-6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyridin-2-amine Chemical compound CC1=C2C=C(C=CC2=NC=N1)C3=C(N=C(C=C3Cl)N)C4=CC=C(C=C4)F MXXFJWVAVZXIJN-UHFFFAOYSA-N 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 7
- BTTKYILNYXUPIP-UHFFFAOYSA-N 6-(4-fluorophenyl)-3-(1-methylpyrazol-4-yl)-5-(4-methylquinazolin-6-yl)pyridin-2-amine Chemical compound CC1=C2C=C(C=CC2=NC=N1)C3=CC(=C(N=C3C4=CC=C(C=C4)F)N)C5=CN(N=C5)C BTTKYILNYXUPIP-UHFFFAOYSA-N 0.000 description 7
- AGKISQXJNFHNPB-UHFFFAOYSA-N 6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)-3-(1H-pyrazol-4-yl)pyridin-2-amine Chemical compound CC1=C2C=C(C=CC2=NC=N1)C3=CC(=C(N=C3C4=CC=C(C=C4)F)N)C5=CNN=C5 AGKISQXJNFHNPB-UHFFFAOYSA-N 0.000 description 7
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- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 7
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- 239000011780 sodium chloride Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- MFRUVSDIZTZFFL-UHFFFAOYSA-N 2-bromo-n,n-dimethylethanamine;hydrobromide Chemical compound [Br-].C[NH+](C)CCBr MFRUVSDIZTZFFL-UHFFFAOYSA-N 0.000 description 6
- 101150051188 Adora2a gene Proteins 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 208000018737 Parkinson disease Diseases 0.000 description 6
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- 238000006482 condensation reaction Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 6
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- IFHTZLJBSTZJAR-UHFFFAOYSA-N 6-(4-fluorophenyl)-3-[1-(2-methoxyethyl)pyrazol-4-yl]-5-(4-methylquinazolin-6-yl)pyridin-2-amine Chemical compound CC1=C2C=C(C=CC2=NC=N1)C3=CC(=C(N=C3C4=CC=C(C=C4)F)N)C5=CN(N=C5)CCOC IFHTZLJBSTZJAR-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- PMXOSAKBCSEPDN-UHFFFAOYSA-N Nc1ccc(Br)c(n1)-c1ccc(F)cc1 Chemical compound Nc1ccc(Br)c(n1)-c1ccc(F)cc1 PMXOSAKBCSEPDN-UHFFFAOYSA-N 0.000 description 5
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- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
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- 230000036737 immune function Effects 0.000 description 1
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- 230000028993 immune response Effects 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
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- 230000008595 infiltration Effects 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- KQEVIFKPZOGBMZ-UHFFFAOYSA-N methyl 3-bromopropanoate Chemical compound COC(=O)CCBr KQEVIFKPZOGBMZ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 239000000296 purinergic P1 receptor antagonist Substances 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HSFQBFMEWSTNOW-UHFFFAOYSA-N sodium;carbanide Chemical group [CH3-].[Na+] HSFQBFMEWSTNOW-UHFFFAOYSA-N 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000023516 stroke disease Diseases 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- XSKZXGDFSCCXQX-UHFFFAOYSA-N thiencarbazone-methyl Chemical compound COC(=O)C1=CSC(C)=C1S(=O)(=O)NC(=O)N1C(=O)N(C)C(OC)=N1 XSKZXGDFSCCXQX-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/02—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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
PCT国内申请，说明书已公开。
Claims (15)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2018116167582 | 2018-12-28 | ||
| CN201811616758 | 2018-12-28 | ||
| CN201910332212 | 2019-04-24 | ||
| CN2019103322122 | 2019-04-24 | ||
| PCT/CN2019/126444 WO2020135195A1 (zh) | 2018-12-28 | 2019-12-19 | 氨基吡啶类化合物及其制备方法和用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113166109A true CN113166109A (zh) | 2021-07-23 |
| CN113166109B CN113166109B (zh) | 2024-01-02 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201980071722.7A Active CN113166109B (zh) | 2018-12-28 | 2019-12-19 | 氨基吡啶类化合物及其制备方法和用途 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US20220017483A1 (zh) |
| EP (1) | EP3904348A4 (zh) |
| CN (1) | CN113166109B (zh) |
| WO (1) | WO2020135195A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023201267A1 (en) | 2022-04-13 | 2023-10-19 | Gilead Sciences, Inc. | Combination therapy for treating trop-2 expressing cancers |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001062233A2 (en) * | 2000-02-25 | 2001-08-30 | F. Hoffmann La Roche Ag | Adenosine receptor modulators |
| WO2002014282A1 (fr) * | 2000-08-11 | 2002-02-21 | Eisai Co., Ltd. | Composes 2-aminopyridine et leur utilisation comme medicaments |
| WO2005100353A1 (en) * | 2004-04-15 | 2005-10-27 | Almirall Prodesfarma, Sa | Condensed pyridine derivatives useful as a28 adenosine receptor antagonists |
| CN1871231A (zh) * | 2003-10-27 | 2006-11-29 | 安斯泰来制药有限公司 | 吡嗪衍生物及其医药用途 |
| ES2303776A1 (es) * | 2006-12-29 | 2008-08-16 | Laboratorios Almirall S.A. | Derivados de 5-fenil-6-piridin-4-il-1,3-dihidro-2h-imidazo(4,5-b)piridin-2-ona utiles como antagonistas del receptor de adenosina a2b. |
| WO2015157093A1 (en) * | 2014-04-08 | 2015-10-15 | Rigel Pharmaceuticals, Inc. | 2,3-disubstituted pyridine compounds as tgf-beta inhibitors and methods of use |
| CN110240593A (zh) * | 2018-03-09 | 2019-09-17 | 四川科伦博泰生物医药股份有限公司 | 取代芳胺化合物及其制备方法和用途 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI330183B (zh) | 2001-10-22 | 2010-09-11 | Eisai R&D Man Co Ltd | |
| US20050043315A1 (en) | 2002-01-02 | 2005-02-24 | Hideo Tsutsumi | Aminopyrimidine compounds, processes for their preparation and pharmaceutical compositions containing them |
| GB0403155D0 (en) | 2004-02-12 | 2004-03-17 | Vernalis Res Ltd | Chemical compounds |
| ES2579949T3 (es) | 2010-02-05 | 2016-08-17 | Heptares Therapeutics Limited | Derivados de 1,2,4-triazin-4-amina |
| JP2020506885A (ja) | 2017-01-13 | 2020-03-05 | 江蘇恒瑞医薬股▲ふん▼有限公司 | １，２，４−トリアジン−３−アミン誘導体、その製造方法、および医薬におけるその使用 |
| WO2020135210A1 (zh) * | 2018-12-28 | 2020-07-02 | 四川科伦博泰生物医药股份有限公司 | 取代芳基化合物及其制备方法和用途 |
-
2019
- 2019-12-19 US US17/289,476 patent/US20220017483A1/en active Pending
- 2019-12-19 CN CN201980071722.7A patent/CN113166109B/zh active Active
- 2019-12-19 WO PCT/CN2019/126444 patent/WO2020135195A1/zh unknown
- 2019-12-19 EP EP19902618.8A patent/EP3904348A4/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001062233A2 (en) * | 2000-02-25 | 2001-08-30 | F. Hoffmann La Roche Ag | Adenosine receptor modulators |
| CN1438890A (zh) * | 2000-02-25 | 2003-08-27 | 弗·哈夫曼-拉罗切有限公司 | 腺苷受体调制剂 |
| WO2002014282A1 (fr) * | 2000-08-11 | 2002-02-21 | Eisai Co., Ltd. | Composes 2-aminopyridine et leur utilisation comme medicaments |
| CN1446202A (zh) * | 2000-08-11 | 2003-10-01 | 卫材株式会社 | 2－氨基吡啶化合物及其作为药物的用途 |
| AU2001277741B2 (en) * | 2000-08-11 | 2005-12-22 | Eisai R&D Management Co., Ltd. | 2-aminopyridine compounds and use thereof as drugs |
| CN1871231A (zh) * | 2003-10-27 | 2006-11-29 | 安斯泰来制药有限公司 | 吡嗪衍生物及其医药用途 |
| WO2005100353A1 (en) * | 2004-04-15 | 2005-10-27 | Almirall Prodesfarma, Sa | Condensed pyridine derivatives useful as a28 adenosine receptor antagonists |
| ES2303776A1 (es) * | 2006-12-29 | 2008-08-16 | Laboratorios Almirall S.A. | Derivados de 5-fenil-6-piridin-4-il-1,3-dihidro-2h-imidazo(4,5-b)piridin-2-ona utiles como antagonistas del receptor de adenosina a2b. |
| WO2015157093A1 (en) * | 2014-04-08 | 2015-10-15 | Rigel Pharmaceuticals, Inc. | 2,3-disubstituted pyridine compounds as tgf-beta inhibitors and methods of use |
| CN110240593A (zh) * | 2018-03-09 | 2019-09-17 | 四川科伦博泰生物医药股份有限公司 | 取代芳胺化合物及其制备方法和用途 |
Non-Patent Citations (2)
| Title |
|---|
| SAREL J. ROBINSON: "2-Aminopyrimidines as dual adenosine A1/A2A antagonists", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY * |
| V. S. PRASADARAO LINGAM: "Design, Synthesis, and Pharmacological Evaluation of 5,6- Disubstituted Pyridin-2(1H)‑one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists", J. MED. CHEM. * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3904348A1 (en) | 2021-11-03 |
| WO2020135195A1 (zh) | 2020-07-02 |
| CN113166109B (zh) | 2024-01-02 |
| US20220017483A1 (en) | 2022-01-20 |
| EP3904348A4 (en) | 2022-10-19 |
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