JP6001053B2 - タンパク質キナーゼ阻害剤 - Google Patents
タンパク質キナーゼ阻害剤 Download PDFInfo
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- JP6001053B2 JP6001053B2 JP2014502963A JP2014502963A JP6001053B2 JP 6001053 B2 JP6001053 B2 JP 6001053B2 JP 2014502963 A JP2014502963 A JP 2014502963A JP 2014502963 A JP2014502963 A JP 2014502963A JP 6001053 B2 JP6001053 B2 JP 6001053B2
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- Prior art keywords
- mmol
- added
- compound
- alkyl
- hydrogen
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- 229940043355 kinase inhibitor Drugs 0.000 title description 4
- 239000003909 protein kinase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 149
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 78
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 38
- 125000003342 alkenyl group Chemical group 0.000 claims description 29
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 29
- 125000000304 alkynyl group Chemical group 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 22
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 21
- 108091000080 Phosphotransferase Proteins 0.000 claims description 20
- 102000020233 phosphotransferase Human genes 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000003112 inhibitor Substances 0.000 claims description 11
- 239000000523 sample Substances 0.000 claims description 10
- 102000001253 Protein Kinase Human genes 0.000 claims description 9
- 108060006633 protein kinase Proteins 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 108010009978 Tec protein-tyrosine kinase Proteins 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 229960002685 biotin Drugs 0.000 claims description 2
- 235000020958 biotin Nutrition 0.000 claims description 2
- 239000011616 biotin Substances 0.000 claims description 2
- 239000002872 contrast media Substances 0.000 claims description 2
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 claims description 2
- 230000005298 paramagnetic effect Effects 0.000 claims description 2
- 108010087686 src-Family Kinases Proteins 0.000 claims description 2
- 102000009076 src-Family Kinases Human genes 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 20
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims 1
- 108010016672 Syk Kinase Proteins 0.000 claims 1
- 102000000551 Syk Kinase Human genes 0.000 claims 1
- 239000013522 chelant Substances 0.000 claims 1
- 229940125846 compound 25 Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 453
- 239000000543 intermediate Substances 0.000 description 387
- 239000000243 solution Substances 0.000 description 192
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 144
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 138
- 238000006243 chemical reaction Methods 0.000 description 137
- 239000012044 organic layer Substances 0.000 description 130
- 239000012267 brine Substances 0.000 description 126
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 126
- 230000002829 reductive effect Effects 0.000 description 123
- 239000007787 solid Substances 0.000 description 117
- 238000000746 purification Methods 0.000 description 105
- 229920006395 saturated elastomer Polymers 0.000 description 95
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 90
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 84
- 235000019270 ammonium chloride Nutrition 0.000 description 69
- 238000010898 silica gel chromatography Methods 0.000 description 67
- 230000015572 biosynthetic process Effects 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- 238000003786 synthesis reaction Methods 0.000 description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 36
- 239000003921 oil Substances 0.000 description 33
- 235000019198 oils Nutrition 0.000 description 33
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 32
- 239000000284 extract Substances 0.000 description 32
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 31
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
- 238000001914 filtration Methods 0.000 description 26
- 239000003039 volatile agent Substances 0.000 description 26
- 235000019441 ethanol Nutrition 0.000 description 24
- 239000002244 precipitate Substances 0.000 description 24
- -1 propylene glycol Chemical compound 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 22
- 239000010410 layer Substances 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 18
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 18
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 17
- 229910000024 caesium carbonate Inorganic materials 0.000 description 17
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 17
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 16
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 16
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 14
- 229910052786 argon Inorganic materials 0.000 description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000012230 colorless oil Substances 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 11
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 10
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 125000003367 polycyclic group Polymers 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 5
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- PSLUFJFHTBIXMW-WYEYVKMPSA-N [(3r,4ar,5s,6s,6as,10s,10ar,10bs)-3-ethenyl-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-6-(2-pyridin-2-ylethylcarbamoyloxy)-5,6,6a,8,9,10-hexahydro-2h-benzo[f]chromen-5-yl] acetate Chemical compound O([C@@H]1[C@@H]([C@]2(O[C@](C)(CC(=O)[C@]2(O)[C@@]2(C)[C@@H](O)CCC(C)(C)[C@@H]21)C=C)C)OC(=O)C)C(=O)NCCC1=CC=CC=N1 PSLUFJFHTBIXMW-WYEYVKMPSA-N 0.000 description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 4
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 4
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 4
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 description 4
- 0 CC*N(*)C(C)=O Chemical compound CC*N(*)C(C)=O 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 4
- QOVYHDHLFPKQQG-NDEPHWFRSA-N N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O Chemical compound N[C@@H](CCC(=O)N1CCC(CC1)NC1=C2C=CC=CC2=NC(NCC2=CN(CCCNCCCNC3CCCCC3)N=N2)=N1)C(O)=O QOVYHDHLFPKQQG-NDEPHWFRSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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- 230000000694 effects Effects 0.000 description 4
- 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 4
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 4
- 150000002894 organic compounds Chemical class 0.000 description 4
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000019491 signal transduction Effects 0.000 description 4
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 description 4
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 3
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- C12N9/10—Transferases (2.)
- C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
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| CA2760174A CA2760174A1 (en) | 2011-12-01 | 2011-12-01 | Protein kinase inhibitors and uses thereof |
| CA2,760,174 | 2011-12-01 | ||
| PCT/CA2012/000333 WO2012135944A1 (en) | 2011-04-04 | 2012-04-03 | Protein kinase inhibitors |
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| JP2014510114A JP2014510114A (ja) | 2014-04-24 |
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| KR20140021629A (ko) * | 2011-04-04 | 2014-02-20 | 파마사이언스 인크. | 단백질 키나제 저해제 |
| BR112015025260B1 (pt) | 2013-04-25 | 2021-11-03 | Beigene, Ltd | Compostos heterocíclicos fundidos como inibidores da proteína quinase, sua composição, combinação e uso |
| HRP20221262T1 (hr) | 2013-09-13 | 2022-12-09 | Beigene Switzerland Gmbh | Protutijela anti-pd1 i njihova uporaba kao terapeutskih i dijagnostičkih sredstava |
| CA2833701A1 (en) * | 2013-11-19 | 2015-05-19 | Pharmascience Inc. | Protein kinase inhibitors |
| EP3076974A1 (en) | 2013-12-05 | 2016-10-12 | Acerta Pharma B.V. | Therapeutic combination of a pi3k inhibitor and a btk inhibitor |
| CN105829321B (zh) * | 2013-12-31 | 2018-01-09 | 靳博涵 | 用于治疗癌症和炎性疾病的化合物 |
| WO2015185998A2 (en) | 2014-04-11 | 2015-12-10 | Acerta Pharma B.V. | Methods of blocking the cxcr-4/sdf-1 signaling pathway with inhibitors of bone marrow x kinase |
| WO2015181633A2 (en) | 2014-04-11 | 2015-12-03 | Acerta Pharma B.V. | Methods of blocking the cxcr-4/sdf-1 signaling pathway with inhibitors of bruton's tyrosine kinase |
| CN110156892B (zh) | 2014-07-03 | 2023-05-16 | 百济神州有限公司 | 抗pd-l1抗体及其作为治疗剂及诊断剂的用途 |
| AR101476A1 (es) | 2014-08-07 | 2016-12-21 | Acerta Pharma Bv | Métodos para tratar cánceres, enfermedades inmunes y autoinmunes, y enfermedades inflamatorias en base a la tasa de ocupación de la tirosin quinasa de bruton (btk) y a la tasa de resíntesis de la tirosin quinasa de bruton (btk) |
| US20170231986A1 (en) | 2014-08-11 | 2017-08-17 | Acerta Pharma B.V. | Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a BCL-2 Inhibitor |
| US20170224819A1 (en) | 2014-08-11 | 2017-08-10 | Acerta Pharma B.V. | Therapeutic Combinations of a BTK Inhibitor, a PI3K Inhibitor, a JAK-2 Inhibitor, and/or a CDK 4/6 Inhibitor |
| EP3179992B1 (en) | 2014-08-11 | 2022-05-11 | Acerta Pharma B.V. | Therapeutic combinations of a btk inhibitor, a pd-1 inhibitor and/or a pd-l1 inhibitor |
| US20170231995A1 (en) | 2014-08-11 | 2017-08-17 | Acerta Pharma B.V. | BTK Inhibitors to Treat Solid Tumors Through Modulation of the Tumor Microenvironment |
| WO2016087994A1 (en) | 2014-12-05 | 2016-06-09 | Acerta Pharma B.V. | Btk inhibitors to treat solid tumors through modulation of the tumor microenvironment |
| WO2017033113A1 (en) | 2015-08-21 | 2017-03-02 | Acerta Pharma B.V. | Therapeutic combinations of a mek inhibitor and a btk inhibitor |
| US20190022092A1 (en) | 2015-09-15 | 2019-01-24 | Acerta Pharma B.V. | Therapeutic Combinations of a BTK Inhibitor and a GITR Binding Molecule, a 4-1BB Agonist, or an OX40 Agonist |
| MA44909A (fr) | 2015-09-15 | 2018-07-25 | Acerta Pharma Bv | Association thérapeutique d'un inhibiteur du cd19 et d'un inhibiteur de la btk |
| EP3402503B1 (en) | 2016-01-13 | 2020-10-21 | Acerta Pharma B.V. | Therapeutic combinations of an antifolate and a btk inhibitor |
| NZ749997A (en) | 2016-07-05 | 2022-11-25 | Beigene Ltd | Combination of a pd-l antagonist and a raf inhibitor for treating cancer |
| WO2018033853A2 (en) | 2016-08-16 | 2018-02-22 | Beigene, Ltd. | Crystalline form of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, preparation, and uses thereof |
| TWI739887B (zh) | 2016-08-19 | 2021-09-21 | 英屬開曼群島商百濟神州有限公司 | 使用包含btk抑制劑的組合產品治療癌症 |
| AU2017326558B2 (en) | 2016-09-19 | 2022-01-06 | Mei Pharma, Inc. | Combination therapy |
| EP3573989A4 (en) | 2017-01-25 | 2020-11-18 | Beigene, Ltd. | CRYSTALLINE FORMS OF (S) -7- (1- (BUT-2-YNOYL) PIPERIDIN-4-YL) -2- (4-PHENOXYPHENYL) -4, 5, 6, 7-TETRAHY DROPYRAZOLO [1, 5-A ] PYRIMIDINE-3-CARBOXAMIDE, PREPARATION AND ASSOCIATED USES |
| TWI877099B (zh) | 2017-06-26 | 2025-03-21 | 英屬開曼群島商百濟神州有限公司 | 抗pd-1抗體或其抗原結合片段在製備治療用於患有肝細胞癌(hcc)之藥物的用途 |
| WO2019034009A1 (en) | 2017-08-12 | 2019-02-21 | Beigene, Ltd. | BTK INHIBITOR WITH ENHANCED DOUBLE SELECTIVITY |
| US11786529B2 (en) | 2017-11-29 | 2023-10-17 | Beigene Switzerland Gmbh | Treatment of indolent or aggressive B-cell lymphomas using a combination comprising BTK inhibitors |
| TWI856111B (zh) | 2019-06-10 | 2024-09-21 | 瑞士商百濟神州瑞士有限責任公司 | 一種含有布魯頓氏酪胺酸激酶抑制劑的口服固體錠劑及其製備方法 |
| WO2023077216A1 (en) * | 2021-11-02 | 2023-05-11 | Bright Angel Therapeutics Inc. | Heat shock protein 90 (hsp90) inhibitors for treating fungal infections and methods of use thereof |
| US11786531B1 (en) | 2022-06-08 | 2023-10-17 | Beigene Switzerland Gmbh | Methods of treating B-cell proliferative disorder |
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| CH643228A5 (en) * | 1979-02-02 | 1984-05-30 | Givaudan & Cie Sa | Process for the preparation of alpha-hydroxycarbonyl compounds |
| DK0552237T3 (da) * | 1990-10-09 | 1993-07-28 | Neurogen Corp | Visse cycloalkyl- og azacycloalkyl-pyrrolopyrimidiner, en klasse af ligander for GABA-receptorer i hjernen |
| JP3465827B2 (ja) | 1993-02-24 | 2003-11-10 | 株式会社日清製粉グループ本社 | アザインドール誘導体およびこれを有効成分とする抗潰瘍薬 |
| ATE159257T1 (de) * | 1994-05-03 | 1997-11-15 | Ciba Geigy Ag | Pyrrolopyrimidinderivate mit antiproliferativer wirkung |
| GB9524346D0 (en) * | 1995-11-29 | 1996-01-31 | Univ Strathclyde | Polycyclic compounds |
| AU3176297A (en) * | 1996-06-25 | 1998-01-14 | Novartis Ag | Substituted 7-amino-pyrrolo{3,2-d}pyrimidines and the use thereof |
| MXPA06013996A (es) | 2004-06-02 | 2007-02-08 | Takeda Pharmaceutical | Compuesto heterociclico fusionado. |
| US7982035B2 (en) | 2007-08-27 | 2011-07-19 | Duquesne University Of The Holy Spirit | Tricyclic compounds having antimitotic and/or antitumor activity and methods of use thereof |
| KR20140021629A (ko) * | 2011-04-04 | 2014-02-20 | 파마사이언스 인크. | 단백질 키나제 저해제 |
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| WO2012135944A1 (en) | 2012-10-11 |
| EP2694517A1 (en) | 2014-02-12 |
| EP2694517A4 (en) | 2014-08-27 |
| WO2012135944A9 (en) | 2014-01-09 |
| US20140045833A1 (en) | 2014-02-13 |
| CA2760174A1 (en) | 2013-06-01 |
| US9624239B2 (en) | 2017-04-18 |
| JP2014510114A (ja) | 2014-04-24 |
| CA2831813A1 (en) | 2012-10-11 |
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