ES2329085T3 - Derivados de (4-(benzo(b)tiofen-2-il)-pirimidin-2-il)-amina como inhibidores de ikk-beta para el tratamiento del cancer y de enfermedades inflamatorias. - Google Patents
Derivados de (4-(benzo(b)tiofen-2-il)-pirimidin-2-il)-amina como inhibidores de ikk-beta para el tratamiento del cancer y de enfermedades inflamatorias. Download PDFInfo
- Publication number
- ES2329085T3 ES2329085T3 ES06850430T ES06850430T ES2329085T3 ES 2329085 T3 ES2329085 T3 ES 2329085T3 ES 06850430 T ES06850430 T ES 06850430T ES 06850430 T ES06850430 T ES 06850430T ES 2329085 T3 ES2329085 T3 ES 2329085T3
- Authority
- ES
- Spain
- Prior art keywords
- benzo
- thiophene
- mmol
- carboxylic acid
- pyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003839 salts Chemical class 0.000 claims abstract description 47
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 46
- 239000001257 hydrogen Substances 0.000 claims abstract description 44
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 13
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 3
- 125000006301 indolyl methyl group Chemical group 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 3
- 125000004950 trifluoroalkyl group Chemical group 0.000 claims abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 8
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- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 31
- MGJXBDMLVWIYOQ-UHFFFAOYSA-N methylazanide Chemical compound [NH-]C MGJXBDMLVWIYOQ-UHFFFAOYSA-N 0.000 claims description 17
- ANCBHJKEYPZCTE-UHFFFAOYSA-N ethyl 5-carbamoyl-4-methyl-2-[(2,3,4,5,6-pentafluorobenzoyl)amino]thiophene-3-carboxylate Chemical compound CC1=C(C(N)=O)SC(NC(=O)C=2C(=C(F)C(F)=C(F)C=2F)F)=C1C(=O)OCC ANCBHJKEYPZCTE-UHFFFAOYSA-N 0.000 claims description 13
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 9
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- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
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- 208000029565 malignant colon neoplasm Diseases 0.000 claims 1
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 abstract description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 713
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 92
- 239000000725 suspension Substances 0.000 description 92
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 78
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 73
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
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- 229910000041 hydrogen chloride Inorganic materials 0.000 description 41
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 38
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 32
- 150000002148 esters Chemical class 0.000 description 32
- 238000001914 filtration Methods 0.000 description 32
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
- 230000002829 reductive effect Effects 0.000 description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 28
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 25
- 238000004587 chromatography analysis Methods 0.000 description 25
- 238000000746 purification Methods 0.000 description 25
- 239000012043 crude product Substances 0.000 description 24
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 21
- 238000001035 drying Methods 0.000 description 21
- 230000008569 process Effects 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 19
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 18
- RGUABPVONIGVAT-UHFFFAOYSA-N 3-(4-methylpiperazin-1-yl)propan-1-amine Chemical compound CN1CCN(CCCN)CC1 RGUABPVONIGVAT-UHFFFAOYSA-N 0.000 description 17
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 17
- 239000007789 gas Substances 0.000 description 17
- 239000012299 nitrogen atmosphere Substances 0.000 description 17
- YNVOMSDITJMNET-UHFFFAOYSA-N thiophene-3-carboxylic acid Chemical compound OC(=O)C=1C=CSC=1 YNVOMSDITJMNET-UHFFFAOYSA-N 0.000 description 17
- 239000002904 solvent Substances 0.000 description 16
- 239000012258 stirred mixture Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- KLBAONGYSCOBHX-UHFFFAOYSA-N 2-[5-chloro-2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-1-benzothiophene-4-carboxylic acid Chemical compound C1CN(C)CCN1CCCNC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(O)=O)=N1 KLBAONGYSCOBHX-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
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- GSQDFHSGLFZEMW-UHFFFAOYSA-N n-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-benzothiophene-4-carboxamide Chemical compound ClC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 GSQDFHSGLFZEMW-UHFFFAOYSA-N 0.000 description 14
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- 238000010992 reflux Methods 0.000 description 14
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- ODQTWTGPDQOEFJ-UHFFFAOYSA-N 2-(2,5-dichloropyrimidin-4-yl)-1-benzothiophene-4-carboxylic acid Chemical compound C=1C=2C(C(=O)O)=CC=CC=2SC=1C1=NC(Cl)=NC=C1Cl ODQTWTGPDQOEFJ-UHFFFAOYSA-N 0.000 description 13
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- 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 12
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- CGVKBSGIGZOHFS-UHFFFAOYSA-N 2-[5-chloro-2-[2-(1-methylpiperidin-4-yl)ethylamino]pyrimidin-4-yl]-1-benzothiophene-4-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1CN(C)CCC1CCNC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(N)=O)=N1 CGVKBSGIGZOHFS-UHFFFAOYSA-N 0.000 description 11
- STNOBDOQYMUVEB-UHFFFAOYSA-N 4-(1-benzothiophen-2-yl)-n-[3-(4-methylpiperazin-1-yl)propyl]pyrimidin-2-amine Chemical compound C1CN(C)CCN1CCCNC1=NC=CC(C=2SC3=CC=CC=C3C=2)=N1 STNOBDOQYMUVEB-UHFFFAOYSA-N 0.000 description 11
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- KFVFPOGBNARWQS-UHFFFAOYSA-N n-cyclopropyl-2-[5-fluoro-2-(3-piperidin-4-ylpropylamino)pyrimidin-4-yl]-1-benzothiophene-4-carboxamide Chemical compound N1=C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)C(F)=CN=C1NCCCC1CCNCC1 KFVFPOGBNARWQS-UHFFFAOYSA-N 0.000 description 9
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 2
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- LJEKEROHNAFUGD-UHFFFAOYSA-N methyl 1-benzothiophene-4-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1C=CS2 LJEKEROHNAFUGD-UHFFFAOYSA-N 0.000 description 2
- LUAQLMFNQYOVPQ-UHFFFAOYSA-N methyl 1-benzothiophene-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=CSC2=C1 LUAQLMFNQYOVPQ-UHFFFAOYSA-N 0.000 description 2
- KWPDOYBIQDYAFZ-UHFFFAOYSA-N methyl 2-(2,5-dichloropyrimidin-4-yl)-1-benzothiophene-6-carboxylate Chemical compound S1C2=CC(C(=O)OC)=CC=C2C=C1C1=NC(Cl)=NC=C1Cl KWPDOYBIQDYAFZ-UHFFFAOYSA-N 0.000 description 2
- KFKSAAAAZWCNTF-UHFFFAOYSA-N methyl 2-(2-chloro-5-methylpyrimidin-4-yl)-1-benzothiophene-6-carboxylate Chemical compound S1C2=CC(C(=O)OC)=CC=C2C=C1C1=NC(Cl)=NC=C1C KFKSAAAAZWCNTF-UHFFFAOYSA-N 0.000 description 2
- WYSBFEHXFISSGN-UHFFFAOYSA-N methyl 2-(2-chloropyrimidin-4-yl)-1-benzothiophene-4-carboxylate Chemical compound C=1C=2C(C(=O)OC)=CC=CC=2SC=1C1=CC=NC(Cl)=N1 WYSBFEHXFISSGN-UHFFFAOYSA-N 0.000 description 2
- PRTPXMSRPUOBDP-UHFFFAOYSA-N methyl 2-[5-chloro-2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-1-benzothiophene-4-carboxylate Chemical compound C=1C=2C(C(=O)OC)=CC=CC=2SC=1C(C(=CN=1)Cl)=NC=1NCCCN1CCN(C)CC1 PRTPXMSRPUOBDP-UHFFFAOYSA-N 0.000 description 2
- ACHZNZUMVVFBHW-UHFFFAOYSA-N methyl 2-[5-chloro-2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-1-benzothiophene-6-carboxylate Chemical compound S1C2=CC(C(=O)OC)=CC=C2C=C1C(C(=CN=1)Cl)=NC=1NCCCN1CCN(C)CC1 ACHZNZUMVVFBHW-UHFFFAOYSA-N 0.000 description 2
- MOYOANKQRNLYLF-UHFFFAOYSA-N methyl 2-[5-methyl-2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-1-benzothiophene-6-carboxylate Chemical compound S1C2=CC(C(=O)OC)=CC=C2C=C1C(C(=CN=1)C)=NC=1NCCCN1CCN(C)CC1 MOYOANKQRNLYLF-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- KOCBLPAULFFOST-UHFFFAOYSA-N n,n-dimethyl-2-[5-methyl-2-[2-(1-methylpiperidin-4-yl)ethylamino]pyrimidin-4-yl]-1-benzothiophene-6-carboxamide;dihydrochloride Chemical compound Cl.Cl.S1C2=CC(C(=O)N(C)C)=CC=C2C=C1C(C(=CN=1)C)=NC=1NCCC1CCN(C)CC1 KOCBLPAULFFOST-UHFFFAOYSA-N 0.000 description 2
- PYBVUVHCDKNZAR-UHFFFAOYSA-N n-[3-[[5-chloro-4-[4-(cyclopropylcarbamoyl)-1-benzothiophen-2-yl]pyrimidin-2-yl]amino]propyl]-1-methylpiperidine-4-carboxamide Chemical compound C1CN(C)CCC1C(=O)NCCCNC1=NC=C(Cl)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 PYBVUVHCDKNZAR-UHFFFAOYSA-N 0.000 description 2
- MWENITABFGJZIJ-UHFFFAOYSA-N n-[[4-(aminomethyl)cyclohexyl]methyl]-4-(1-benzothiophen-2-yl)pyrimidin-2-amine Chemical compound C1CC(CN)CCC1CNC1=NC=CC(C=2SC3=CC=CC=C3C=2)=N1 MWENITABFGJZIJ-UHFFFAOYSA-N 0.000 description 2
- IFHXMLXGQUKVSB-UHFFFAOYSA-N n-cyclopropyl-2-[5-methyl-2-(3-piperidin-3-ylpropylamino)pyrimidin-4-yl]-1-benzothiophene-4-carboxamide Chemical compound N1=C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)C(C)=CN=C1NCCCC1CCCNC1 IFHXMLXGQUKVSB-UHFFFAOYSA-N 0.000 description 2
- HSUAOOWDEZTLIJ-UHFFFAOYSA-N n-cyclopropyl-2-[5-methyl-2-(3-piperidin-4-ylpropylamino)pyrimidin-4-yl]-1-benzothiophene-4-carboxamide Chemical compound N1=C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)C(C)=CN=C1NCCCC1CCNCC1 HSUAOOWDEZTLIJ-UHFFFAOYSA-N 0.000 description 2
- AWQVKAURKXXOCG-UHFFFAOYSA-N n-cyclopropylformamide Chemical compound O=CNC1CC1 AWQVKAURKXXOCG-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- IIKFXOLJMNWWCH-UHFFFAOYSA-N piperidine-1,4-dicarboxylic acid Chemical compound OC(=O)C1CCN(C(O)=O)CC1 IIKFXOLJMNWWCH-UHFFFAOYSA-N 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical class [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
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- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
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- 230000000707 stereoselective effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
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- AJTYGHSVRUDXKS-UHFFFAOYSA-N tert-butyl 3-(3-aminopropyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(CCCN)C1 AJTYGHSVRUDXKS-UHFFFAOYSA-N 0.000 description 2
- UHLAQCKNCBYTIF-UHFFFAOYSA-N tert-butyl 3-propan-2-ylpiperazine-1-carboxylate Chemical compound CC(C)C1CN(C(=O)OC(C)(C)C)CCN1 UHLAQCKNCBYTIF-UHFFFAOYSA-N 0.000 description 2
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- XXDVSPISMICMLG-UHFFFAOYSA-N tert-butyl 4-(2-cyano-1-hydroxyethyl)-4-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(C(O)CC#N)CC1 XXDVSPISMICMLG-UHFFFAOYSA-N 0.000 description 2
- RUVUXLNBUSXMDH-UHFFFAOYSA-N tert-butyl 4-(2-cyanoacetyl)-4-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(C(=O)CC#N)CC1 RUVUXLNBUSXMDH-UHFFFAOYSA-N 0.000 description 2
- JDAXWOQUXAAJHV-UHFFFAOYSA-N tert-butyl 4-(3-aminopropyl)-3-propan-2-ylpiperazine-1-carboxylate Chemical compound CC(C)C1CN(C(=O)OC(C)(C)C)CCN1CCCN JDAXWOQUXAAJHV-UHFFFAOYSA-N 0.000 description 2
- RORXMFNDHUAQSA-UHFFFAOYSA-N tert-butyl 4-(3-aminopropyl)-4-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(CCCN)CC1 RORXMFNDHUAQSA-UHFFFAOYSA-N 0.000 description 2
- PRMYRRODTPOYIU-UHFFFAOYSA-N tert-butyl 4-(cyanomethyl)-4-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(CC#N)CC1 PRMYRRODTPOYIU-UHFFFAOYSA-N 0.000 description 2
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- UZLNKOXBXNATQR-UHFFFAOYSA-N tert-butyl 4-[3-[[4-(4-methoxycarbonyl-1-benzothiophen-2-yl)pyrimidin-2-yl]amino]propyl]piperazine-1-carboxylate Chemical compound C=1C=2C(C(=O)OC)=CC=CC=2SC=1C(N=1)=CC=NC=1NCCCN1CCN(C(=O)OC(C)(C)C)CC1 UZLNKOXBXNATQR-UHFFFAOYSA-N 0.000 description 2
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- GAPQRLMAHSWQML-UHFFFAOYSA-N n-[3-[[5-chloro-4-[4-(cyclopropylcarbamoyl)-1-benzothiophen-2-yl]pyrimidin-2-yl]amino]propyl]piperidine-4-carboxamide Chemical compound N1=C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)C(Cl)=CN=C1NCCCNC(=O)C1CCNCC1 GAPQRLMAHSWQML-UHFFFAOYSA-N 0.000 description 1
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- HFOWVIHUKBABOV-KRWDZBQOSA-N n-cyclopropyl-2-[5-methyl-2-[3-[(2s)-2-methylpiperazin-1-yl]propylamino]pyrimidin-4-yl]-1-benzothiophene-4-carboxamide Chemical compound C[C@H]1CNCCN1CCCNC1=NC=C(C)C(C=2SC3=CC=CC(=C3C=2)C(=O)NC2CC2)=N1 HFOWVIHUKBABOV-KRWDZBQOSA-N 0.000 description 1
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- IYKIHDRDNJDVHU-INIZCTEOSA-N n-methyl-2-[5-methyl-2-[3-[(2s)-2-methylpiperazin-1-yl]propylamino]pyrimidin-4-yl]-1-benzothiophene-4-carboxamide Chemical compound C=1C=2C(C(=O)NC)=CC=CC=2SC=1C(C(=CN=1)C)=NC=1NCCCN1CCNC[C@@H]1C IYKIHDRDNJDVHU-INIZCTEOSA-N 0.000 description 1
- IFSZEBQWBWOLKA-INIZCTEOSA-N n-methyl-2-[5-methyl-2-[3-[(3s)-3-methylpiperazin-1-yl]propylamino]pyrimidin-4-yl]-1-benzothiophene-4-carboxamide Chemical compound C=1C=2C(C(=O)NC)=CC=CC=2SC=1C(C(=CN=1)C)=NC=1NCCCN1CCN[C@@H](C)C1 IFSZEBQWBWOLKA-INIZCTEOSA-N 0.000 description 1
- GEMDSWZIFPIWFZ-UHFFFAOYSA-N n-methyl-3-[2-[2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-1-benzothiophen-6-yl]benzamide Chemical compound CNC(=O)C1=CC=CC(C=2C=C3SC(=CC3=CC=2)C=2N=C(NCCCN3CCN(C)CC3)N=CC=2)=C1 GEMDSWZIFPIWFZ-UHFFFAOYSA-N 0.000 description 1
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- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 229940080469 phosphocellulose Drugs 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 125000005543 phthalimide group Chemical class 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000006485 reductive methylation reaction Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 238000007789 sealing Methods 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
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
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- SNLWYFMDXBEOGE-LLVKDONJSA-N tert-butyl (3r)-4-(3-aminopropyl)-3-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CCCN SNLWYFMDXBEOGE-LLVKDONJSA-N 0.000 description 1
- ZRYDCWWNCKKREA-UHFFFAOYSA-N tert-butyl 3-(3-methylsulfonyloxypropyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(CCCOS(C)(=O)=O)C1 ZRYDCWWNCKKREA-UHFFFAOYSA-N 0.000 description 1
- IKEURFVSAUCQQW-UHFFFAOYSA-N tert-butyl 4-(2-cyano-1-methylsulfonyloxyethyl)-4-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(C(CC#N)OS(C)(=O)=O)CC1 IKEURFVSAUCQQW-UHFFFAOYSA-N 0.000 description 1
- KGIVNBCHQVUGMM-UHFFFAOYSA-N tert-butyl 4-(3-amino-1-hydroxypropyl)-4-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(C(O)CCN)CC1 KGIVNBCHQVUGMM-UHFFFAOYSA-N 0.000 description 1
- SQJTVQSZFVOIQV-UHFFFAOYSA-N tert-butyl 4-(3-bromopropyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CCCBr)CC1 SQJTVQSZFVOIQV-UHFFFAOYSA-N 0.000 description 1
- GPLDUALYAYSMEE-UHFFFAOYSA-N tert-butyl 4-methyl-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C)(COS(C)(=O)=O)CC1 GPLDUALYAYSMEE-UHFFFAOYSA-N 0.000 description 1
- BEYPLCFQKGMXOY-UHFFFAOYSA-N tert-butyl 5-(2-aminoethyl)-2,3,3a,4,6,6a-hexahydro-1h-pyrrolo[3,4-c]pyrrole-3-carboxylate Chemical compound C1N(CCN)CC2C(C(=O)OC(C)(C)C)NCC21 BEYPLCFQKGMXOY-UHFFFAOYSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- RKRXZHZDUUMIKY-UHFFFAOYSA-N tert-butyl n-[2-(2-chloro-5-methylpyrimidin-4-yl)-1-benzothiophen-6-yl]carbamate Chemical compound CC1=CN=C(Cl)N=C1C1=CC2=CC=C(NC(=O)OC(C)(C)C)C=C2S1 RKRXZHZDUUMIKY-UHFFFAOYSA-N 0.000 description 1
- MRORCVDHNJKPPY-UHFFFAOYSA-N tert-butyl n-[[2-(2-chloropyrimidin-4-yl)-1-benzothiophen-6-yl]methyl]carbamate Chemical compound S1C2=CC(CNC(=O)OC(C)(C)C)=CC=C2C=C1C1=CC=NC(Cl)=N1 MRORCVDHNJKPPY-UHFFFAOYSA-N 0.000 description 1
- SRJCQOUDPCYNIB-UHFFFAOYSA-N tert-butyl n-[[2-[2-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]-1-benzothiophen-6-yl]methyl]carbamate Chemical compound C1CN(C)CCN1CCCNC1=NC=CC(C=2SC3=CC(CNC(=O)OC(C)(C)C)=CC=C3C=2)=N1 SRJCQOUDPCYNIB-UHFFFAOYSA-N 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- YPPDPANYMIUZJG-UHFFFAOYSA-N tert-butyl thiophene-3-carboxylate Chemical compound CC(C)(C)OC(=O)C=1C=CSC=1 YPPDPANYMIUZJG-UHFFFAOYSA-N 0.000 description 1
- TWRVYXVQOJCHIF-UHFFFAOYSA-N tert-butyl-chloro-methylsilane Chemical compound C[SiH](Cl)C(C)(C)C TWRVYXVQOJCHIF-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical class CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
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- Tropical Medicine & Parasitology (AREA)
- Pain & Pain Management (AREA)
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- Orthopedic Medicine & Surgery (AREA)
- Pulmonology (AREA)
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| US73809705P | 2005-11-18 | 2005-11-18 | |
| US738097P | 2005-11-18 |
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| KR101054325B1 (ko) | 2006-03-31 | 2011-08-04 | 얀센 파마슈티카 엔.브이. | 히스타민 ｈ４ 수용체 조절제로서의 벤조이미다졸―２―일 피리미딘 및 피라진 |
| CN101790527A (zh) * | 2006-07-20 | 2010-07-28 | 凯利普西斯公司 | Rho激酶的苯并噻吩抑制剂 |
| WO2008076705A1 (en) * | 2006-12-21 | 2008-06-26 | Eli Lilly And Company | Imidazolidinonyl aminopyrimidine compounds for the treatment of cancer |
| JP5166441B2 (ja) * | 2006-12-21 | 2013-03-21 | イーライ リリー アンド カンパニー | 癌治療用イミダゾリジノニルアミノピリミジン化合物 |
| JP5248600B2 (ja) | 2007-05-16 | 2013-07-31 | イーライ リリー アンド カンパニー | トリアゾリルアミノピリミジン化合物 |
| AU2008254318B2 (en) | 2007-05-16 | 2012-04-05 | Eli Lilly And Company | Triazolyl aminopyrimidine compounds |
| EP2310012B1 (en) | 2008-06-30 | 2015-03-04 | Janssen Pharmaceutica N.V. | Process for the preparation of substituted pyrimidine derivatives |
| US9371311B2 (en) | 2008-06-30 | 2016-06-21 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine derivatives |
| KR101123178B1 (ko) * | 2009-04-09 | 2012-06-13 | (주)에스메디 | 2-아릴벤조싸이오펜 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 퇴행성 뇌질환의 진단 또는 치료용 약학적 조성물 |
| KR20120059558A (ko) | 2009-08-19 | 2012-06-08 | 암비트 바이오사이언시즈 코포레이션 | 바이아릴 화합물 및 이의 사용 방법 |
| KR20130069641A (ko) | 2010-04-27 | 2013-06-26 | 허치슨 메디파르마 리미티드 | 피리미디닐 인돌 화합물 |
| EP2694707B1 (en) | 2011-04-07 | 2018-08-15 | Cornell University | Monomers capable of dimerizing in an aqueous solution, and methods of using same |
| US9245773B2 (en) | 2011-09-02 | 2016-01-26 | Taiwan Semiconductor Manufacturing Company, Ltd. | Semiconductor device packaging methods and structures thereof |
| CN103159742B (zh) * | 2011-12-16 | 2015-08-12 | 北京韩美药品有限公司 | 5-氯嘧啶类化合物及其作为egfr酪氨酸激酶抑制剂的应用 |
| AU2013216935C1 (en) | 2012-02-08 | 2017-12-14 | John Emmerson Campbell | Heteroaryl compounds and methods of use thereof |
| US9227978B2 (en) | 2013-03-15 | 2016-01-05 | Araxes Pharma Llc | Covalent inhibitors of Kras G12C |
| TWI659021B (zh) | 2013-10-10 | 2019-05-11 | 亞瑞克西斯製藥公司 | Ｋｒａｓ ｇ１２ｃ之抑制劑 |
| CN105085434B (zh) * | 2014-05-09 | 2018-02-09 | 上海特化医药科技有限公司 | 硫乙拉嗪或其中间体的制备方法 |
| WO2017076888A1 (en) | 2015-11-03 | 2017-05-11 | Janssen Pharmaceutica Nv | 2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carboxylic acids and amides and methods of making the same |
| ES2996835T3 (en) | 2016-07-29 | 2025-02-13 | Sumitomo Pharma America Inc | Compounds and compositions and uses thereof |
| MA45795A (fr) | 2016-07-29 | 2019-06-05 | Sunovion Pharmaceuticals Inc | Composés et compositions, et utilisations associées |
| WO2018140512A1 (en) | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Fused bicyclic benzoheteroaromatic compounds and methods of use thereof |
| US11136308B2 (en) | 2017-01-26 | 2021-10-05 | Araxes Pharma Llc | Substituted quinazoline and quinazolinone compounds and methods of use thereof |
| WO2018140599A1 (en) * | 2017-01-26 | 2018-08-02 | Araxes Pharma Llc | Benzothiophene and benzothiazole compounds and methods of use thereof |
| US11279689B2 (en) | 2017-01-26 | 2022-03-22 | Araxes Pharma Llc | 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer |
| KR20200010306A (ko) | 2017-05-25 | 2020-01-30 | 아락세스 파마 엘엘씨 | Kras의 공유적 억제제 |
| US11639346B2 (en) | 2017-05-25 | 2023-05-02 | Araxes Pharma Llc | Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS |
| AU2018312559B2 (en) | 2017-08-02 | 2022-06-02 | Pgi Drug Discovery Llc | Isochroman compounds and uses thereof |
| US12134620B2 (en) | 2018-08-01 | 2024-11-05 | Araxes Pharma Llc | Heterocyclic spiro compounds and methods of use thereof for the treatment of cancer |
| WO2020186165A1 (en) | 2019-03-14 | 2020-09-17 | Sunovion Pharmaceuticals Inc. | Salts of a isochromanyl compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof |
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| AU3752589A (en) * | 1988-05-16 | 1989-12-12 | Georgia State University Research Foundation, Inc. | Nucleic acid interacting unfused heteropolycyclic compounds |
| GB0308466D0 (en) * | 2003-04-11 | 2003-05-21 | Novartis Ag | Organic compounds |
| MX2007007032A (es) * | 2004-12-17 | 2007-07-04 | Amgen Inc | Compuestos de aminopirimidina y metodos de uso. |
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2006
- 2006-10-23 TW TW095139053A patent/TW200800201A/zh unknown
- 2006-11-15 PL PL06850430T patent/PL1989200T3/pl unknown
- 2006-11-15 ES ES06850430T patent/ES2329085T3/es active Active
- 2006-11-15 DK DK06850430T patent/DK1989200T3/da active
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- 2006-11-15 DE DE602006008187T patent/DE602006008187D1/de active Active
- 2006-11-15 JP JP2008541463A patent/JP2009516697A/ja not_active Ceased
- 2006-11-15 AT AT06850430T patent/ATE437873T1/de active
- 2006-11-15 CA CA002629336A patent/CA2629336A1/en not_active Abandoned
- 2006-11-15 WO PCT/US2006/060911 patent/WO2007092095A2/en not_active Ceased
- 2006-11-15 CN CN2006800428126A patent/CN101309918B/zh not_active Expired - Fee Related
- 2006-11-15 SI SI200630446T patent/SI1989200T1/sl unknown
- 2006-11-15 PT PT06850430T patent/PT1989200E/pt unknown
- 2006-11-15 EA EA200801362A patent/EA014426B1/ru not_active IP Right Cessation
- 2006-11-15 BR BRPI0618245-3A patent/BRPI0618245A2/pt not_active IP Right Cessation
- 2006-11-15 AU AU2006337626A patent/AU2006337626B2/en not_active Ceased
- 2006-11-15 US US12/093,024 patent/US7547691B2/en not_active Expired - Fee Related
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- 2006-11-15 KR KR1020087011830A patent/KR100990771B1/ko not_active Expired - Fee Related
- 2006-11-17 AR ARP060105065A patent/AR057911A1/es unknown
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2008
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- 2008-04-29 CR CR9947A patent/CR9947A/es not_active Application Discontinuation
- 2008-05-08 ZA ZA200803940A patent/ZA200803940B/xx unknown
- 2008-05-16 EC EC2008008456A patent/ECSP088456A/es unknown
- 2008-05-16 TN TNP2008000227A patent/TNSN08227A1/en unknown
- 2008-06-10 NO NO20082594A patent/NO20082594L/no not_active Application Discontinuation
- 2008-06-13 MA MA31035A patent/MA30053B1/fr unknown
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