CN103936757B - 五元并六元杂环化合物、其制备方法、药物组合物和应用 - Google Patents
五元并六元杂环化合物、其制备方法、药物组合物和应用 Download PDFInfo
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- CN103936757B CN103936757B CN201410022938.3A CN201410022938A CN103936757B CN 103936757 B CN103936757 B CN 103936757B CN 201410022938 A CN201410022938 A CN 201410022938A CN 103936757 B CN103936757 B CN 103936757B
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- compound
- heterocyclylalkyl
- added
- alkyl
- base
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- 150000000644 6-membered heterocyclic compounds Chemical class 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- -1 preparation method Substances 0.000 claims abstract description 129
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 201000010099 disease Diseases 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
- 230000004663 cell proliferation Effects 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 497
- 125000005842 heteroatom Chemical group 0.000 claims description 61
- 125000003118 aryl group Chemical group 0.000 claims description 52
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 42
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 42
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 37
- 229910052760 oxygen Inorganic materials 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 35
- 125000001072 heteroaryl group Chemical group 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 125000002252 acyl group Chemical group 0.000 claims description 30
- 239000001301 oxygen Substances 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 229910052740 iodine Inorganic materials 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000004442 acylamino group Chemical group 0.000 claims description 10
- 125000001118 alkylidene group Chemical group 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 8
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 7
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 229950002366 nafoxidine Drugs 0.000 claims description 6
- 230000002265 prevention Effects 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000005936 piperidyl group Chemical group 0.000 claims description 5
- 150000003217 pyrazoles Chemical class 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000003566 oxetanyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 230000006641 stabilisation Effects 0.000 claims description 4
- 238000011105 stabilization Methods 0.000 claims description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 3
- 150000000660 7-membered heterocyclic compounds Chemical class 0.000 claims 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 2
- 125000006594 (C1-C3) alkylsulfony group Chemical group 0.000 claims 1
- 229940122245 Janus kinase inhibitor Drugs 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 150000002391 heterocyclic compounds Chemical class 0.000 claims 1
- 102000015617 Janus Kinases Human genes 0.000 abstract description 21
- 108010024121 Janus Kinases Proteins 0.000 abstract description 21
- 206010028980 Neoplasm Diseases 0.000 abstract description 11
- 201000011510 cancer Diseases 0.000 abstract description 8
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 230000002503 metabolic effect Effects 0.000 abstract description 7
- 102000020233 phosphotransferase Human genes 0.000 abstract description 7
- 239000002243 precursor Substances 0.000 abstract description 7
- 229940002612 prodrug Drugs 0.000 abstract description 7
- 239000000651 prodrug Substances 0.000 abstract description 7
- 239000002207 metabolite Substances 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 230000002159 abnormal effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 425
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 398
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 396
- 239000002585 base Substances 0.000 description 246
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 232
- 239000000243 solution Substances 0.000 description 202
- 238000003786 synthesis reaction Methods 0.000 description 196
- 230000015572 biosynthetic process Effects 0.000 description 195
- 239000000203 mixture Substances 0.000 description 172
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 150
- 238000006243 chemical reaction Methods 0.000 description 143
- 239000000706 filtrate Substances 0.000 description 135
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 132
- 239000007787 solid Substances 0.000 description 126
- 239000012074 organic phase Substances 0.000 description 117
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 106
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 100
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 92
- 238000005160 1H NMR spectroscopy Methods 0.000 description 84
- 239000000047 product Substances 0.000 description 75
- 239000012266 salt solution Substances 0.000 description 72
- 229920006395 saturated elastomer Polymers 0.000 description 72
- 238000010898 silica gel chromatography Methods 0.000 description 69
- 239000012299 nitrogen atmosphere Substances 0.000 description 65
- 238000003756 stirring Methods 0.000 description 62
- 238000001914 filtration Methods 0.000 description 60
- 239000012071 phase Substances 0.000 description 60
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 56
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 56
- 239000007864 aqueous solution Substances 0.000 description 55
- 239000007791 liquid phase Substances 0.000 description 55
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 54
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 54
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- 238000000605 extraction Methods 0.000 description 50
- 229940125898 compound 5 Drugs 0.000 description 49
- 230000006837 decompression Effects 0.000 description 46
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 235000019441 ethanol Nutrition 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000002904 solvent Substances 0.000 description 36
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 34
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
- 229910052799 carbon Inorganic materials 0.000 description 30
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 29
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 28
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 26
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 23
- 229910000027 potassium carbonate Inorganic materials 0.000 description 22
- XORHNJQEWQGXCN-UHFFFAOYSA-N 4-nitro-1h-pyrazole Chemical compound [O-][N+](=O)C=1C=NNC=1 XORHNJQEWQGXCN-UHFFFAOYSA-N 0.000 description 21
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
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- 239000012895 dilution Substances 0.000 description 17
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- SHPHYIMDOLOPIB-UHFFFAOYSA-N 2,3-dibenzylidene-1H-indene Chemical class C(C1=CC=CC=C1)=C1C(C2=CC=CC=C2C1)=CC1=CC=CC=C1 SHPHYIMDOLOPIB-UHFFFAOYSA-N 0.000 description 16
- 238000004587 chromatography analysis Methods 0.000 description 16
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- 239000000725 suspension Substances 0.000 description 16
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- 238000001556 precipitation Methods 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
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- 238000001819 mass spectrum Methods 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
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- LBGSWBJURUFGLR-UHFFFAOYSA-N 1-methylpyrazol-4-amine Chemical compound CN1C=C(N)C=N1 LBGSWBJURUFGLR-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
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- 150000007529 inorganic bases Chemical class 0.000 description 6
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- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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Abstract
Description
Claims (29)
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EP (1) | EP2947084B8 (zh) |
JP (1) | JP6321039B2 (zh) |
CN (1) | CN103936757B (zh) |
DK (1) | DK2947084T3 (zh) |
ES (1) | ES2827233T3 (zh) |
HK (1) | HK1215567A1 (zh) |
WO (1) | WO2014111037A1 (zh) |
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WO2014111037A1 (zh) | 2013-01-18 | 2014-07-24 | 上海昀怡健康管理咨询有限公司 | 五元并六元杂环化合物、其制备方法、药物组合物和应用 |
CN104177363B (zh) * | 2013-05-24 | 2018-06-05 | 江苏先声药业有限公司 | 双环杂环胺类Hedgehog信号通路抑制剂 |
KR20190135464A (ko) * | 2016-12-01 | 2019-12-06 | 압토스 바이오사이언시스 인코포레이티드 | Brd4 및 jak2 이중 억제제로서의 융합된 피리미딘 및 이의 사용 방법 |
KR102398659B1 (ko) | 2017-03-17 | 2022-05-16 | 주식회사 대웅제약 | 카이네이즈 저해제로서의 피롤로트리아진 유도체 |
CN110446713B (zh) * | 2018-06-06 | 2022-05-24 | 杭州澳津生物医药技术有限公司 | 一种吡唑嘧啶衍生物及其用途和药物组合物 |
CA3129665A1 (en) | 2019-03-21 | 2020-09-24 | Onxeo | A dbait molecule in combination with kinase inhibitor for the treatment of cancer |
CN111943959A (zh) * | 2019-05-17 | 2020-11-17 | 上海再极医药科技有限公司 | 一种jak抑制剂的合成方法 |
CN110305140B (zh) * | 2019-07-30 | 2020-08-04 | 上海勋和医药科技有限公司 | 二氢吡咯并嘧啶类选择性jak2抑制剂 |
CN110862380A (zh) * | 2019-10-24 | 2020-03-06 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物 |
KR20220098759A (ko) | 2019-11-08 | 2022-07-12 | 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) | 키나제 억제제에 대해 내성을 획득한 암의 치료 방법 |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
WO2022020887A1 (en) * | 2020-07-27 | 2022-02-03 | Esfam Biotech Pty Ltd | Treatment of cd151 related disorders |
WO2022020890A1 (en) * | 2020-07-27 | 2022-02-03 | Esfam Biotech Pty Ltd | Treatment of veterinary conditions associated with cd151 |
WO2022129376A1 (en) | 2020-12-18 | 2022-06-23 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | 6-6 or 5-6 fused bicyclic compounds comprising a pyri(mi)dine ring useful in the|treatment of infectious diseases |
CN114181076A (zh) * | 2021-12-23 | 2022-03-15 | 维思普新材料(苏州)有限公司 | 一种2,6-二卤代苯甲酸甲酯的制备方法 |
TW202339715A (zh) * | 2022-04-08 | 2023-10-16 | 大陸商深圳再極醫藥科技有限公司 | 一種含jak抑制劑的藥物組合物及其製備方法和用途 |
WO2024041397A1 (en) * | 2022-08-22 | 2024-02-29 | Hangzhou Highlightll Pharmaceutical Co., Ltd | Jak1/jak2/tyk2 inhibitors for topical treatment of dermatological diseases |
WO2024051771A1 (zh) * | 2022-09-08 | 2024-03-14 | 广州再极医药科技有限公司 | 一种五元并六元杂环化合物的晶型及其制备方法和应用 |
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2014
- 2014-01-17 WO PCT/CN2014/070778 patent/WO2014111037A1/zh active Application Filing
- 2014-01-17 EP EP14740886.8A patent/EP2947084B8/en active Active
- 2014-01-17 JP JP2015552995A patent/JP6321039B2/ja active Active
- 2014-01-17 US US14/761,772 patent/US9745320B2/en active Active
- 2014-01-17 ES ES14740886T patent/ES2827233T3/es active Active
- 2014-01-17 DK DK14740886.8T patent/DK2947084T3/da active
- 2014-01-20 CN CN201410022938.3A patent/CN103936757B/zh active Active
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2016
- 2016-03-24 HK HK16103485.8A patent/HK1215567A1/zh unknown
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Also Published As
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EP2947084B1 (en) | 2020-09-23 |
US9745320B2 (en) | 2017-08-29 |
ES2827233T3 (es) | 2021-05-20 |
DK2947084T3 (da) | 2020-11-02 |
WO2014111037A1 (zh) | 2014-07-24 |
US20150336982A1 (en) | 2015-11-26 |
HK1215567A1 (zh) | 2016-09-02 |
JP2016505025A (ja) | 2016-02-18 |
CN103936757A (zh) | 2014-07-23 |
EP2947084A4 (en) | 2016-10-05 |
JP6321039B2 (ja) | 2018-05-09 |
EP2947084A1 (en) | 2015-11-25 |
EP2947084B8 (en) | 2021-03-10 |
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