CN112585138A - 可用于治疗癌症的作为ErbB调节剂的4-取代的吡咯并[2,3-b]吡啶 - Google Patents
可用于治疗癌症的作为ErbB调节剂的4-取代的吡咯并[2,3-b]吡啶 Download PDFInfo
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- CN112585138A CN112585138A CN201980055136.3A CN201980055136A CN112585138A CN 112585138 A CN112585138 A CN 112585138A CN 201980055136 A CN201980055136 A CN 201980055136A CN 112585138 A CN112585138 A CN 112585138A
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- Prior art keywords
- pyrrolo
- phenyl
- pyridin
- methylphenyl
- methylpiperazin
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- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims description 139
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 92
- 239000000203 mixture Substances 0.000 claims description 79
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 44
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 41
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 28
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- 229910052763 palladium Inorganic materials 0.000 claims description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 21
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
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- LOVSBQNXYCBEBX-UHFFFAOYSA-N 1-[7-[4-chloro-2-[3-[(4-methylpiperazin-1-yl)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C1=CC(=CC=C1)CN1CCN(CC1)C LOVSBQNXYCBEBX-UHFFFAOYSA-N 0.000 claims description 2
- SQTAWWOAEOUGHC-UHFFFAOYSA-N 1-[7-[4-chloro-2-[3-[2-(dimethylamino)ethoxy]phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C1=CC(=CC=C1)OCCN(C)C SQTAWWOAEOUGHC-UHFFFAOYSA-N 0.000 claims description 2
- BQPDRHPYSAWKND-UHFFFAOYSA-N 1-[7-[4-chloro-2-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C1=CC=C(C=C1)N1CCN(CC1)C BQPDRHPYSAWKND-UHFFFAOYSA-N 0.000 claims description 2
- MCZSAEZJTAQLLJ-UHFFFAOYSA-N 1-[7-[4-chloro-2-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C1=CC=C(C=C1)N1CCN(CC1)C(C)C MCZSAEZJTAQLLJ-UHFFFAOYSA-N 0.000 claims description 2
- OVNVLEGKBYHKNR-UHFFFAOYSA-N 1-[7-[4-chloro-2-[4-[2-(dimethylamino)ethoxy]phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C1=CC=C(C=C1)OCCN(C)C OVNVLEGKBYHKNR-UHFFFAOYSA-N 0.000 claims description 2
- VNYASIKCLZVFAV-UHFFFAOYSA-N 1-[7-[4-chloro-2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C=1C=NC(=CC=1)N1CCN(CC1)C VNYASIKCLZVFAV-UHFFFAOYSA-N 0.000 claims description 2
- JJESJGIAVBSCJZ-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)O)C1=CC=C(C=C1)N1CCN(CC1)C JJESJGIAVBSCJZ-UHFFFAOYSA-N 0.000 claims description 2
- QMQITAVZVDDCEM-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-N-propan-2-yl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)NC(C)C)C1=CC=C(C=C1)N1CCN(CC1)C QMQITAVZVDDCEM-UHFFFAOYSA-N 0.000 claims description 2
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- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
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- LWFCZIOZUYXFTB-UHFFFAOYSA-N methyl 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC)C1=CC=C(C=C1)N1CCN(CC1)C LWFCZIOZUYXFTB-UHFFFAOYSA-N 0.000 claims description 2
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- YVTNVVHZUGWSJF-UHFFFAOYSA-N propan-2-yl 2-[3-[(dimethylamino)methyl]phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC(C)C)C1=CC(=CC=C1)CN(C)C YVTNVVHZUGWSJF-UHFFFAOYSA-N 0.000 claims description 2
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- OLMGWELATOBARC-SNAWJCMRSA-N (E)-N-[5-[4-chloro-2-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-methylphenyl]but-2-enamide Chemical compound ClC1=C2C(=NC=C1)NC(=C2C=1C=CC(=C(C=1)NC(\C=C\C)=O)C)C1=CC=C(C=C1)N1CCN(CC1)C OLMGWELATOBARC-SNAWJCMRSA-N 0.000 claims 2
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- ZGMJVTCQYODUEF-UHFFFAOYSA-N 1-[6-[4-methoxy-2-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-2,3-dihydroindol-1-yl]prop-2-en-1-one Chemical compound COC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCN(C2=C1)C(C=C)=O)C1=CC(=NC=C1)N1CCN(CC1)C ZGMJVTCQYODUEF-UHFFFAOYSA-N 0.000 claims 1
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- MBJMEFYDOSPSSB-UHFFFAOYSA-N 1-[7-[4-chloro-2-[3-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C1=CC(=CC=C1)OCCN1CCCC1 MBJMEFYDOSPSSB-UHFFFAOYSA-N 0.000 claims 1
- DLHHGTIPAGQXCY-UHFFFAOYSA-N 1-[7-[4-chloro-2-[4-(1-methylpiperidin-4-yl)phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C1=CC=C(C=C1)C1CCN(CC1)C DLHHGTIPAGQXCY-UHFFFAOYSA-N 0.000 claims 1
- ZWFVGAGPBVXKGD-UHFFFAOYSA-N 1-[7-[4-chloro-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C1=CC=C(C=C1)OCCN1CCCC1 ZWFVGAGPBVXKGD-UHFFFAOYSA-N 0.000 claims 1
- QAKOKWQLXXCNQO-UHFFFAOYSA-N 1-[7-[4-chloro-2-[6-[(4-methylpiperazin-1-yl)methyl]pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one Chemical compound ClC1=C2C(=NC=C1)NC(=C2C1=CC=C2CCCN(C2=C1)C(C=C)=O)C=1C=NC(=CC=1)CN1CCN(CC1)C QAKOKWQLXXCNQO-UHFFFAOYSA-N 0.000 claims 1
- KEFZCYGLNPNTJS-UHFFFAOYSA-N 2-[2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]acetic acid Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)CC(=O)O)C1=CC=C(C=C1)N1CCN(CC1)C KEFZCYGLNPNTJS-UHFFFAOYSA-N 0.000 claims 1
- FEEATSPSDDVOOS-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-N-(2-pyridin-4-ylethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)NCCC1=CC=NC=C1)C1=CC=C(C=C1)N1CCN(CC1)C FEEATSPSDDVOOS-UHFFFAOYSA-N 0.000 claims 1
- JVOHGUVIGPZIBQ-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)NCC=1C=NC=CC=1)C1=CC=C(C=C1)N1CCN(CC1)C JVOHGUVIGPZIBQ-UHFFFAOYSA-N 0.000 claims 1
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- VSKVYTKDTKNJAV-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-N-[(3-sulfamoylphenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)NCC1=CC(=CC=C1)S(N)(=O)=O)C1=CC=C(C=C1)N1CCN(CC1)C VSKVYTKDTKNJAV-UHFFFAOYSA-N 0.000 claims 1
- MTKAXLJYFKOENW-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-N-[(4-methyl-1,2,4-triazol-3-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)NCC1=NN=CN1C)C1=CC=C(C=C1)N1CCN(CC1)C MTKAXLJYFKOENW-UHFFFAOYSA-N 0.000 claims 1
- UVTMFPPXZLFZDM-UHFFFAOYSA-N 2-[4-(4-methylpiperazin-1-yl)phenyl]-N-[(1-methylpiperidin-4-yl)methyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)NCC1CCN(CC1)C)C1=CC=C(C=C1)N1CCN(CC1)C UVTMFPPXZLFZDM-UHFFFAOYSA-N 0.000 claims 1
- JALQBGNQJYPFQO-UHFFFAOYSA-N 2-[4-[2-(dimethylamino)ethyl-methylamino]phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)O)C1=CC=C(C=C1)N(C)CCN(C)C JALQBGNQJYPFQO-UHFFFAOYSA-N 0.000 claims 1
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- YDBLBHOLVADPLA-UHFFFAOYSA-N 2-methyl-N-[2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]propanamide Chemical compound C(C(C)C)(=O)NC=1C=C2C(=NC=1)NC(=C2C=1C=CC(=C(C=1)NC(C=C)=O)C)C1=CC=C(C=C1)N1CCN(CC1)C YDBLBHOLVADPLA-UHFFFAOYSA-N 0.000 claims 1
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- WSWPLBSJKHVPNF-UHFFFAOYSA-N N-benzyl-2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)NCC1=CC=CC=C1)C1=CC=C(C=C1)N1CCN(CC1)C WSWPLBSJKHVPNF-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- PLMKCOLCEDJLFO-UHFFFAOYSA-N cyclobutyl 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC1CCC1)C1=CC=C(C=C1)N1CCN(CC1)C PLMKCOLCEDJLFO-UHFFFAOYSA-N 0.000 claims 1
- PTIOMDFBFIUDCS-UHFFFAOYSA-N cyclohexyl 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC1CCCCC1)C1=CC=C(C=C1)N1CCN(CC1)C PTIOMDFBFIUDCS-UHFFFAOYSA-N 0.000 claims 1
- VHCFDIUKWYJLTK-UHFFFAOYSA-N cyclopentyl 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC1CCCC1)C1=CC=C(C=C1)N1CCN(CC1)C VHCFDIUKWYJLTK-UHFFFAOYSA-N 0.000 claims 1
- ZXIWWXATLIWHEG-UHFFFAOYSA-N cyclopropyl 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC1CC1)C1=CC=C(C=C1)N1CCN(CC1)C ZXIWWXATLIWHEG-UHFFFAOYSA-N 0.000 claims 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims 1
- WZUCEWAEEHYFTM-UHFFFAOYSA-N oxetan-3-yl 2-[2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]acetate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)CC(=O)OC1COC1)C1=CC=C(C=C1)N1CCN(CC1)C WZUCEWAEEHYFTM-UHFFFAOYSA-N 0.000 claims 1
- HDARZDCDAGMEGD-UHFFFAOYSA-N oxetan-3-yl 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC1COC1)C1=CC=C(C=C1)N1CCN(CC1)C HDARZDCDAGMEGD-UHFFFAOYSA-N 0.000 claims 1
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- WIJJPNWJPVOLSJ-UHFFFAOYSA-N propan-2-yl 2-[2-(4-methylpiperazin-1-yl)pyridin-4-yl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC(C)C)C1=CC(=NC=C1)N1CCN(CC1)C WIJJPNWJPVOLSJ-UHFFFAOYSA-N 0.000 claims 1
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- VLDSOPDWIHUXQT-UHFFFAOYSA-N propan-2-yl 2-[4-(2-hydroxyethoxy)phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC(C)C)C1=CC=C(C=C1)OCCO VLDSOPDWIHUXQT-UHFFFAOYSA-N 0.000 claims 1
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- MSJQOUCUVMJAKP-UHFFFAOYSA-N propan-2-yl 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[2-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C(=C(C=CC=1)C1=C(NC2=NC=C(C=C21)C(=O)OC(C)C)C1=CC=C(C=C1)N1CCN(CC1)C)C MSJQOUCUVMJAKP-UHFFFAOYSA-N 0.000 claims 1
- XSBXRGFHWXNNQG-UHFFFAOYSA-N propan-2-yl 2-[4-(4-methylpiperazin-1-yl)phenyl]-3-[3-[(prop-2-enoylamino)methyl]phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NCC=1C=C(C=CC=1)C1=C(NC2=NC=C(C=C21)C(=O)OC(C)C)C1=CC=C(C=C1)N1CCN(CC1)C XSBXRGFHWXNNQG-UHFFFAOYSA-N 0.000 claims 1
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- AVRDIBRPEZUBEJ-UHFFFAOYSA-N propan-2-yl 2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC(C)C)C1=CC=C(C=C1)CN1CCN(CC1)C AVRDIBRPEZUBEJ-UHFFFAOYSA-N 0.000 claims 1
- IOXBYGVRQXMDLG-UHFFFAOYSA-N propan-2-yl 2-[4-[(dimethylamino)methyl]phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC(C)C)C1=CC=C(C=C1)CN(C)C IOXBYGVRQXMDLG-UHFFFAOYSA-N 0.000 claims 1
- FUXSZGVHFLACOU-UHFFFAOYSA-N propan-2-yl 2-[4-[2-(dimethylamino)ethoxy]phenyl]-3-[2-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C(=C(C=CC=1)C1=C(NC2=NC=C(C=C21)C(=O)OC(C)C)C1=CC=C(C=C1)OCCN(C)C)C FUXSZGVHFLACOU-UHFFFAOYSA-N 0.000 claims 1
- FGWBXSPUIMAHCD-UHFFFAOYSA-N propan-2-yl 2-[4-[2-(dimethylamino)ethoxy]phenyl]-3-[4-methyl-3-(prop-2-enoylamino)phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylate Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)C1=C(NC2=NC=C(C=C21)C(=O)OC(C)C)C1=CC=C(C=C1)OCCN(C)C FGWBXSPUIMAHCD-UHFFFAOYSA-N 0.000 claims 1
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- WCJYTPVNMWIZCG-UHFFFAOYSA-N xylylcarb Chemical compound CNC(=O)OC1=CC=C(C)C(C)=C1 WCJYTPVNMWIZCG-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- 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
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P35/00—Antineoplastic agents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
Abstract
Description
本发明涉及某些式(I)的4-取代的1H-吡咯并[2,3-b]吡啶化合物及其药学上可接受的盐。这些化合物可用于治疗或预防通过ErbB受体的某些突变形式(尤其是外显子20Her2和EGFR突变)介导的疾病或医学病症。
技术领域
本发明涉及某些式(I)的4-取代的1H-吡咯并[2,3-b]吡啶化合物及其药学上可接受的盐。这些化合物可用于治疗或预防通过ErbB受体的某些突变形式(尤其是外显子20Her2和EGFR突变)介导的疾病或医学病症。
背景技术
受体酪氨酸激酶(RTK)是传递来自细胞外环境的信号以控制细胞的生长、分化和存活的细胞表面受体。已经发现由基因缺失、突变或扩增引起的蛋白激酶的表达失调对肿瘤的发生和进展(涉及癌细胞增殖、存活、运动和侵袭以及肿瘤血管生成和化学疗法抗性)是重要的。由于对它们的关键作用的深入了解,蛋白激酶是新疗法的重要靶标,尤其对于癌症而言(Hananhan等人.Cell 2000,7,100(1):57-70;Blume-Jensen等人,Nature 2001,17,411(6835):355-65)。
在人类中,受体酪氨酸激酶家族ErbB包含四个成员:EGFR(Her1)、ErbB2(Her2)、ErbB3(Her3)和ErbB4(Her4)。配体的结合会诱导受体的构象变化以形成同源和异源二聚化。Her2的细胞外结构域在没有配体结合的情况下已经在构象上固定,其类似其它配体激活的ErbB成员且因此充当其它配体结合的ErbB的优选二聚化配偶体(partner)。受体的二聚化会激活内在的激酶活性并从而产生其底物的磷酸化,从而导致细胞内多个下游途径的激活,包括抗细胞凋亡的/存活的PI3K-AKT-mTOR和促有丝分裂的RAS-RAF-MEK-ERK-MAPK途径(Chong等人.Nature Med.2013;19(11):1389-1400)。
ErbB激酶家族在人类癌症中的牵涉存在有力先例,因为在癌症(例如乳腺癌(breast cancer)、肺癌、头癌、颈癌和膀胱癌)中普遍发现ErbB的过表达和/或突变。第一代小分子EGFR抑制剂(如特罗凯(厄洛替尼)和易瑞沙(吉非替尼),二者均可逆地结合EGFR)目前是非小细胞肺癌患者的一线疗法,所述患者的肿瘤携带在外显子19和21中的EGFR突变(如L858R和delE746-A750)。第二代和第三代小分子EGFR抑制剂已被设计为不可逆的EGFR抑制剂。这些化合物(例如阿法替尼、HKI-272、CI-1033、EKB-569、WZ-4002、AZ9291、CO-1686)不可逆地结合EGFR,优选地结合半胱氨酸797。
据报道,在美国大约10%的具有NSCLC的患者具有肿瘤相关的EGFR突变(Lynch等人.N Engl J Med.2004,350(21):2129-39)。EGFR突变主要发生在EGFR外显子18-21内(Yasuda等人.Sci Transl Med.2013,18,5(216):216ra177;Leduc等人.Annals ofOncology2017,28,11:2715–2724;Arcila等人.Mol Cancer Ther.2013,12(2):220-229)。这些突变会增加EGFR的激酶活性,从而导致下游促存活信号途径的过度活化(Pao等人.NatRev Cancer 2010,10:760-774)。据报道,EGFR外显子20插入占所有EGFR突变体肺肿瘤的大约4-9.2%(Arcila等人.Mol Cancer Ther.2013,12(2):220-9;Oxnard等人.J ThoracOncol.2013,8(2):179–184;Yasuda等人.Lancet Oncol.2012,13(1):e23-31)。大多数EGFR外显子20插入发生在编码外显子20的氨基酸767至774的区域中,该区域是在EGFR的激酶结构域的C螺旋之后的环内。在用吉非替尼、厄洛替尼或阿法替尼的治疗过程中,带有EGFR外显子20插入突变的肿瘤患者的分析大多数表现出进行性疾病(Yasuda等人.LancetOncol.2012,13(1):e23-31;Yasuda等人.Sci Transl Med.2013,18,5(216):216ra177)。
据报道Her2突变存在于约2-4%的NSCLC中(Buttitta等人.Int J Cancer.2006,119:2586-2591)。最常见的突变是在外显子20内的框架内插入。在83%的具有Her2相关的NSCLC的患者中,四个氨基酸YVMA插入突变发生在Her2的外显子20的密码子775处(Arcila等人.Clin Cancer Res 2012,18:4910-4918)。Her2外显子20插入导致增加的激酶活性和增强的通过下游途径的信号传导,从而导致增加的存活、侵袭力和致瘤性(Wang等人.Cancer Cell 2006;10:25-38)。带有Her2 YVMA突变的肿瘤在很大程度上对已知的EGFR抑制剂具有抗性(Arcila等人.Clin Cancer Res 2012,18:4910-4918)。
本发明的目的是提供作为突变体选择性的ErbB抑制剂(特别是对于外显子20EGFR/Her2突变)的化合物和/或可以用作药学活性剂的其药学上可接受的盐,以及其用于预防和/或治疗细胞增殖性疾病、尤其是癌症的用途,包含本发明的化合物和至少一种抗癌药物的组合;以及包含那些化合物和/或其药学上可接受的盐中的至少一种作为药学活性成分的组合物。
本发明提供了新的化合物,其是突变体选择性的ErbB抑制剂,特别是对于外显子20EGFR/Her2突变,且另外是其它突变体如EGFR T790ML858R突变的抑制剂。
独立权利要求的教导解决了本发明的目的。根据本申请的从属权利要求、说明书、附图和实施例,本发明的其它有利特征、方面和细节是显而易见的。
发明内容
本发明提供了表现出HER2外显子20A775_G776insYVMA(和类似突变)和/或EGFR外显子20H773_V774insNPH(和类似突变)的抑制的化合物。本发明提供了这样的化合物:其为突变体选择性的ErbB抑制剂,特别是对于外显子20EGFR/Her2突变,且另外是其它突变体如EGFR T790ML858R突变的抑制剂。在某些实施方案中,本发明涉及对EGFR和Her2的外显子20为突变体特异性的化合物。在一个方面,本发明提供了包含不可逆的激酶抑制剂的化合物。所述化合物共价地修饰EGFR/Her2中的半胱氨酸797/805。
作为药物活性成分的本发明的化合物和/或其药学上可接受的盐可以用于治疗和/或预防细胞增殖性疾病。
所述细胞增殖性疾病选自乳腺癌、结肠癌、前列腺癌、肺癌、胃癌、卵巢癌、子宫内膜癌、肾癌、肝细胞癌、甲状腺癌、子宫癌、食管癌、鳞状细胞癌、白血病、骨肉瘤、黑素瘤、胶质母细胞瘤和神经母细胞瘤。在一个特别优选的实施方案中,所述障碍选自乳腺癌、胶质母细胞瘤、肾癌、非小细胞肺癌(NSCLC)和黑素瘤。所述化合物也适合用于预防和/或治疗其它过度增殖障碍,特别是良性过度增殖障碍诸如良性前列腺增生。
因而,本发明涉及式(I)的化合物或其对映异构体、对映异构体的混合物、非对映异构体、非对映异构体的混合物、互变异构体、前药、水合物、溶剂化物或药学上可接受的盐
其中
A代表
B代表
R1代表-H、-R*、-CH2-R*、-CHRa-R*、-CRaRb-R*、-CH2CH2-R*、-CRaRb-CRcRd-R*、-CH=CH-R*、-CRa=CRb-R*、-CH2CH2CH2-R*或-CRaRb-CRcRd-CReRf-R*;
Ra-Rf彼此独立地代表-H、-F、-Cl、-CH3、-OCH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2或-环-C3H5;
R*代表-H、-F、-Cl、-Br、-I、-OH、-CN、-NH2、-NHCH3、-NHC2H5、-NHC3H7、-NHCH(CH3)2、-NHC(CH3)3、-N(CH3)2、-N(C2H5)2、-N(C3H7)2、-N[CH(CH3)2]2、-N[C(CH3)3]2、-NO2、-OCH3、-OC2H5、OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-O-环-C3H5、-OCH2-环-C3H5、-O-C2H4-环-C3H5、-CHO、-COCH3、-COC2H5、-COC3H7、-COCH(CH3)2、-COC(CH3)3、-OOC-CH3、-OOC-C2H5、-OOC-C3H7、-OOC-CH(CH3)2、-OOC-环-C3H5、-OOC-环-C3H5、-OCF3、-OC2F5、-NHCOCH3、-NHCOCH(CH3)2、-NHSO2CH3、-NHSO2C2H5、-NHSO2C3H7、-NHSO2CH(CH3)2、-NHSO2-环-C3H5、-SOCH3、-SO2CH3、-SO2CF3、-SO2C2H5、-SO2CH2CF3、-SO2C3H7、-SO2CH(CH3)2、-SO2-环-C3H5、-SO(NH)CH3、-SO(NH)C2H5、-SO(NH)C3H7、-SO(NH)CH(CH3)2、-SO(NH)-环-C3H5、-SO(NCH3)CH3、-SO(NCH3)C2H5、-SO(NCH3)C3H7、-SO(NCH3)CH(CH3)2、-SO(NCH3)-环-C3H5、
R2代表-H、-F、-Cl、-Br、-I、-OH、-CN、-CH3、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-O-环-C3H5、-OCH2-环-C3H5或-O-C2H4-环-C3H5;
R3代表-H、-CH3、-C2H4OH、-OC2H4OH、-NR27R28、-CH2NR27R28、-CH2CH2NR27R28、-CH2CH2CH2NR27R28、-NHCOR27、-NHSO2R27、-OCH2NR27R28、-OCH2CH2NR27R28、-OCH2CH2CH2NR27R28、-NR29CH2NR27R28、-NR29CH2CH2NR27R28、-NR29CH2CH2CH2NR27R28、-CONR27R28、-CONHCH2NR27R28、-CONHCH2CH2NR27R28、-CONH CH2CH2CH2NR27R28、
L是键、-CH2-、-CH(CH3)-、-CH2CH2-、-CH2CH2CH2-、-CF2-、-CF2CH2-、-OCH2-、-OCH2CH2-、-OCH2CH2CH2-、-NHCH2-、-NHCH2CH2-、-NHCH2CH2CH2-、-N(CH3)CH2-、-N(CH3)CH2CH2-、-N(CH3)CH2CH2CH2-、-NHCO-、-NHCOCH2-、-NHCOCH2CH2-、-CO-、-CH2CO-、-CH2CH2CO-、-COCH2-、-COCH2CH2-、-COCH2CO-、-COCH2CH2CO-、-CONH-、-CONHCH2-、-CONHCH2CH2-、-CONHCH2CH2CH2-、-OCO-、-SO2-、-CH2OCO-或-CH2CH2OCO-;
R4代表-H、-CH3或-C2H5;
R5代表
R8-R11彼此独立地代表-H、-F、-Cl、-CN、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-OCH2CH(CH3)2、-OC2H4OCH3、-CH2OCH3、-CH3、-CF3、-C2H5或-C3H7,
或者R8和R9或R9和R10一起形成-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2OCH2-、-CH2OCH2CH2-、-OCH2O-或-OCH2CH2O-;
R12-R16彼此独立地代表-H、-F、-Cl、-CN、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-OCH2CH(CH3)2、-OC2H4OCH3、-CH2OCH3、-CH3、-CF3、-C2H5或-C3H7;
R17-R21彼此独立地代表-H、-F、-Cl、-CN、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-OCH2CH(CH3)2、-OC2H4OCH3、-CH2OCH3、-CH3、-CF3、-C2H5或-C3H7;
R22代表-H、-CH3、-CF3、-C2H5、-C3H7、-COCH3、-COC2H5、-SO2CH3或-SO2C2H5;
R23代表-H、-CH3、-CF3、-C2H5、-C3H7、-CH2CH2OCH3或-C4H9;
R24和R25彼此独立地代表-H、-CH3、-CF3、-C2H5、-C3H7、-CH2CH2OCH3、-CH(CH3)2、-C4H9、-环-C3H5、-环-C4H7、-环-C5H9、-环-C6H11、
或者R24和R25一起形成-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2OCH2-或-CH2OCH2CH2-;
L1代表键、-CH2-、-CH2CH2-或-CH2CH2CH2-;
R26代表-H、-CH3、-C2H5、-C3H7、-CH2CH2OCH3、-CH(CH3)2、-C4H9、-环-C3H5、-环-C4H7、-环-C5H9、-环-C6H11、-C(CH3)3、-Ph或-CH2Ph;
R27-R31彼此独立地代表-H、-F、-Cl、-OH、-CN、-NH2、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-CH3、-CF3、-C2H5、-C3H7、-CH2CH2OCH3、-CH(CH3)2、-C4H9、-环-C3H5、-环-C4H7、-环-C5H9、或-环-C6H11;
R32、R37、R38和R43彼此独立地代表-H、-CH3、-CF3、-C2H5、-C3H7、-CH(CH3)2、-Ph、-CH2Ph、-COCH3、-COCF3、-COC2H5、-COCH(CH3)2、-COC(CH3)3、-COPh、-CO2CH3、-CO2C2H5、-CO2CH(CH3)2、-CO2C(CH3)3、-CO2Ph、-CO2CH2Ph、-SO2CH3、-SO2C2H5、-SO2CF3、或-SO2Ph;
R33、R34、R35和R36彼此独立地代表-H、-CH3、-CF3、-C2H5、-C3H7、-CH(CH3)2、-CN、-NO2、-COCH3、-COC2H5、-COC3H7、-COCH(CH3)2、-COC(CH3)3、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COOCH(CH3)2或-COOC(CH3)3;
R39代表-F、-Br、-Cl、或-I;
R40、R41和R42彼此独立地代表-H、-F、-Cl、-OH、-CN、-NH2、-CH3、-CF3、-C2H5、-C3H7、-CH(CH3)2、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-COCH3、-COCF3、-COC2H5、-COCH(CH3)2、-NHCH3、-NHC2H5、-N(CH3)2、-N(C2H5)2、-NHCOCH3、-NHCOCF3、-NHCOC2H5、-NHCOCH(CH3)2、-CO2H、-CO2CH3、-CO2C2H5、-CO2CH(CH3)2、-CO2Ph、-CO2CH2Ph、-CONH2、-CONHCH3、-CONHC2H5、-CONHCH(CH3)2、-CON(CH3)2、-SO2CH3、-SO2C2H5、-SO2CF3、-SO2Ph、-SO2NH2、-SO2NHCH3、
优选的是式(I)的化合物,其中
A代表
B代表
且R8-R21具有与本文中定义的相同的含义。
也优选的是式(I)的化合物,其中
B代表
且R8-R11和R16-R21具有如本文中定义的含义。
更优选的是式(I)的化合物,其中
B代表
且R9-R10和R16-R21具有如本文中定义的含义。
更优选的是式(I)的化合物,其中
B代表
R8-R11和R16-R21具有如本文中定义的含义。
更优选的是式(I)的化合物,其中所述化合物具有式(Ia)或(Ib):
其中
且R1、R2、R3、R4和R5具有与本文中定义的相同的含义。
更优选的是式(I)、(Ia)和(Ib)中的任一个的化合物,其中
R1代表-H、-CN、-C2H5、-OC2H5、-OCF3、-CH2OH、-COOH、-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2OCH3、-COO-环-C3H5、-COO-环-C4H7、-COO-环-C5H9、-COO-环-C6H11、-CONHCH(CH3)2、-CONH-环-C6H11、-CH2COOH、-CH2COOCH3、-CH2COOCH(CH3)2、-CH2CONH(CH3)、-CH2CON(CH3)2、-NHCOCH3、-NHCOCH(CH3)2、
R2代表-H、-Cl、-CH3、-OCH3、-OC2H5或-OCH(CH3)2;
B代表
R3代表-H、-CH2N(CH3)2、-CH2CH2N(CH3)2、-OCH2CH2N(CH3)2、-OCH2CH2CH2N(CH3)2、-CH2N(CH3)2、-NHCOCH3、-NHSO2CH3、-N(CH3)CH2CH2N(CH3)2、-CONH-环-C3H5、-CONH-环-C6H11、-CONHCH2CH2N(CH3)CH2Ph、-CH2CH2OH、-OCH2CH2OH、
L是键、-CH2-、-OCH2CH2-、-CO-、-CONH-、-SO2-或-CONHCH2CH2CH2-;和
R32代表-H、-CH3、-C2H5、-CH(CH3)2、-CH2Ph、-COCH3或-SO2C2H5。
在某些方面,上述的化合物是式(II)和(III)的化合物:
其中B、R1、R2、R3和R5具有与本文中定义的相同的含义。
优选的是式(II)的化合物,其中
B代表
R3代表-H、-CH2N(CH3)2、-CH2CH2N(CH3)2、-OCH2CH2N(CH3)2、-OCH2CH2CH2N(CH3)2、-CH2N(CH3)2、-NHCOCH3、-NHSO2CH3、-N(CH3)CH2CH2N(CH3)2、-CONH-环-C3H5、-CONH-环-C6H11、-CONHCH2CH2N(CH3)CH2Ph、-CH2CH2OH、-OCH2CH2OH、
L是键、-CH2-、-OCH2CH2-、-CO-、-CONH-、-SO2-或-CONHCH2CH2CH2-;和
R32代表-H、-CH3、-C2H5、-CH(CH3)2、-CH2Ph、-COCH3或-SO2C2H5。
其中
R1、R2、R3和R5具有与上面定义相同的含义;
当n是1或2时,X代表CH2;或者
当n是2时,X代表O;
优选的是式(III)的化合物,其中
B代表
也优选的是式(IIIa)、(IIIb)和(IIIc)中的任一个的化合物:
其中,B、R1、R2、R3和R5具有在式(I)中定义的相同的含义。
更优选的是式(II-1)-(II-6)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf-1)-(IIf-3)、(IIIa-1)-(IIIa-5)、(IIIb-1)-(IIIb-5)和(IIIc-1)-(IIIc-5)中的任一个的化合物。
其中,R1、R2、R3、R5、R20和R21具有如在式(I)中定义的含义。
在式(II-1)-(II-6)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf-1)-(IIf-3)、(IIIa-1)-(IIIa-5)、(IIIb-1)-(IIIb-5)、(IIIc-1)-(IIIc-5)中的任一个中,优选地,R1代表-H、-CN、-C2H5、-OC2H5、-OCF3、-CH2OH、-COOH、-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2OCH3、-COO-环-C3H5、-COO-环-C4H7、-COO-环-C5H9、-COO-环-C6H11、-CONHCH(CH3)2、-CONH-环-C6H11、-CH2COOH、-CH2COOCH3、-CH2COOCH(CH3)2、-CH2CONH(CH3)、-CH2CON(CH3)2、-NHCOCH3、-NHCOCH(CH3)2、
R2代表-H、-Cl、-CH3、-OCH3、-OC2H5或-OCH(CH3)2;
R3代表-H、-CH2N(CH3)2、-CH2CH2N(CH3)2、-OCH2CH2N(CH3)2、-OCH2CH2CH2N(CH3)2、-CH2N(CH3)2、-NHCOCH3、-NHSO2CH3、-N(CH3)CH2CH2N(CH3)2、-CONH-环-C3H5、-CONH-环-C6H11、-CONHCH2CH2N(CH3)CH2Ph、-CH2CH2OH、-OCH2CH2OH、
L是键、-CH2-、-OCH2CH2-、-CO-、-CONH-、-SO2-或-CONHCH2CH2CH2-;且
R32代表-H、-CH3、-C2H5、-CH(CH3)2、-CH2Ph、-COCH3或-SO2C2H5。
特别优选的根据本发明的化合物包括由表1呈现的化合物。
表1
或上述化合物的对映异构体、对映异构体的混合物、非对映异构体、非对映异构体的混合物、互变异构体、前药、水合物、溶剂化物或其药学上可接受的盐。
表述前药定义为以无活性或明显较低低活性的形式应用的物质。一旦施用并掺入,前药在体内代谢为活性化合物。用于选择和制备合适的前药衍生物的常规规程描述于例如“Design of Prodrugs”,H.B.Bundgaard编,Elsevier,1985。
本发明在它的范围内还包括上面式(I)的化合物的N-氧化物。一般而言,这样的N-氧化物可以通过常规方式形成,诸如在湿氧化铝存在下使式(I)的化合物与臭氧(oxone)反应。
表述互变异构体定义为通过称为互变异构化的化学反应可相互转化的有机化合物。互变异构化可以优选地由碱或酸或其它合适的化合物催化。
本发明的化合物可以与有机或无机酸或碱形成盐。用于这样的酸加成盐形成的合适酸的例子是盐酸、氢溴酸、硫酸、磷酸、乙酸、柠檬酸、草酸、丙二酸、水杨酸、对氨基水杨酸、苹果酸、富马酸、琥珀酸、抗坏血酸、马来酸、磺酸、膦酸、高氯酸、硝酸、甲酸、丙酸、葡糖酸、乳酸、酒石酸、羟基马来酸、丙酮酸、苯乙酸、苯甲酸、对氨基苯甲酸、对羟基苯甲酸、甲磺酸、乙磺酸、亚硝酸、羟基乙磺酸、亚乙基磺酸、对甲苯磺酸、萘基磺酸、对氨基苯磺酸、樟脑磺酸、中国酸(china acid)、扁桃酸、邻甲基扁桃酸、氢-苯磺酸、苦味酸、己二酸、D-邻甲苯基酒石酸、羟基丙二酸、(邻、间、对)-甲苯甲酸、萘基胺磺酸、三氟乙酸和本领域技术人员众所周知的其它无机酸或羧酸。如下制备盐:以本领域技术人员众所周知的常规方式,使式(I)的化合物的游离碱形式与足够量的所需酸接触以产生盐。
本发明的化合物可以以许多不同的多晶型形式存在。
在本发明的化合物带有酸性基团的情况下,也可以与无机或有机碱形成盐。合适的无机或有机碱的例子是例如NaOH、KOH、NH4OH、四烷基氢氧化铵、赖氨酸或精氨酸等。可以使用本领域众所周知的方法以常规方式制备盐,例如通过用选自上述组中的酸溶液处理通式(I)的化合物的溶液。
发明人发现,为了获得对肝微粒体表现出代谢稳定性的抑制剂,必须取代挨着弹头(warhead)的苯环处的2-位。所述弹头可以是丁-2-烯酰胺、4-(二甲基氨基)丁-2-烯酰胺、丙炔酰胺、乙烯磺酰胺、丙烯酰胺或2-氯-乙酰胺残基。挨着弹头的苯环处的2-位必须不同于氢,并且优选地是烷基或亚烷基(alkylenyl)残基,诸如甲基(如在化合物编号1-54、72-82、116-148中),或可以是环系统的一部分,所述环系统优选地含有弹头的氮原子(如在化合物编号55-71、83-95、98-115中)。没有该取代基,尤其是没有该-CH3或-CH2-取代基,就无法实现针对肝微粒体的代谢稳定性,因此在体内无法获得药物活性。
化合物的合成
通过参考在下述方案1-4中所示的方法,制备式(I)的化合物。通过合适选择具有适当取代的试剂,通过方案1-3生产式(I)的化合物。本领域普通技术人员可以容易地选择溶剂、温度、压强和其它反应条件。起始原料是商购可得的,或由本领域普通技术人员容易地制备。
如在方案1中所示,本发明涉及一种生产式(Ia-1)的化合物的方法,其包括:
步骤A1:在第一钯催化剂和第一碱的存在下,执行吡啶化合物1*与炔烃化合物2a*的第一交叉偶联反应
以得到化合物3*
步骤B1:将化合物3*的三甲基甲硅烷基转化成卤化物如碘化物以得到化合物4*
步骤C1:在第二钯催化剂和第二碱的存在下,执行4*与化合物5*的第二交叉偶联反应
以得到化合物6*
步骤D1:将化合物6*的硝基(NO2)基团还原成伯胺(NH2)基团以得到化合物7*;和
步骤E1:执行化合物7*
与化合物HO-R5或AG-R5的偶联反应以得到式(Ia-1)的产物化合物
化合物1*具有下式
其中R1、R2具有与在式(I)中所定义相同的含义;
X是离去基团且代表Cl、Br、I或OTf。
方案1
可替换地,第二交叉偶联反应的顺序,硝基的还原和进一步偶联反应可以变化,且因此通过下述方法得到产物化合物Ia-1。
一种用于生产式(Ia-1)的化合物的方法,其包括(方案2):
步骤A1:在第一钯催化剂和第一碱的存在下,执行吡啶化合物1*与炔烃化合物2a*的第一交叉偶联反应
以得到化合物3*
步骤D2:将化合物3*的硝基(NO2)基团还原成伯胺(NH2)基团以得到化合物10*
步骤E2:执行化合物10*与化合物HO-R5或AG-R5的偶联反应以得到化合物11*
步骤B2:将化合物11*的三甲基甲硅烷基转化成卤化物如碘化物以得到化合物12*
步骤C2:在第二钯催化剂和第二碱的存在下,执行化合物12*与化合物5*的第二交叉偶联反应以得到式(Ia-1)的产物化合物
方案2
本发明的另一个方面是在方案3中描述的一种用于生产式(Ib)的化合物的方法。
一种用于生产式(Ib)的化合物的方法,其包括:
步骤A3:
i)在第一钯催化剂和第一碱的存在下,执行吡啶化合物1*
与炔烃化合物2b*的第一交叉偶联反应
ii)除去在步骤i)以后得到的化合物的保护基PG以得到化合物3b*
步骤E3:执行化合物3b*与化合物HO-R5或AG-R5的偶联反应以得到化合物11b*
步骤B3:将化合物11b*的三甲基甲硅烷基转化成卤化物如碘化物以得到化合物12b*
步骤C3:在第二钯催化剂和第二碱的存在下,执行化合物12b*与化合物5*的第二交叉偶联反应
以得到式(Ib)的产物化合物
方案3
在方案4中描述了用于生产式(Ia-1)的化合物的另一种方法。
用于生产式(Ia-1)的化合物的另一种方法包括:
步骤A4:在第一钯催化剂和第一碱的存在下,执行吡啶化合物1*
与炔烃化合物2b*的第一交叉偶联反应
以得到化合物13*
步骤B4:将化合物13*的三甲基甲硅烷基转化成卤化物如碘化物以得到化合物14*
步骤C4:在第二钯催化剂和第二碱的存在下,执行化合物14*与化合物5*的第二交叉偶联反应
以得到化合物15*
步骤E4:
i)除去化合物15*的保护基PG;
ii)执行在步骤i)以后得到的化合物与化合物HO-R5或AG-R5的偶联反应以得到式(Ib)的产物化合物。
方案4
X是离去基团且代表Cl、Br、I或OTf;
AG是羧酸的活化基团;
PG是氨基保护基;
TMS是三甲基甲硅烷基;和
R′是H或具有1-10个碳原子的烷基链或具有3-12个碳原子的环烷基链,或两个残基R′一起代表从频哪醇衍生出的残基。
在步骤A1、A3和A4中的每一个中,在第一钯催化剂和碱存在下进行化合物1*的Sonogashia偶联反应和得到的偶联化合物的多米诺环化。任选地,铜催化剂可以用作共催化剂,且优选是Cu(I),且更优选是CuI。
C-C偶联反应的第一钯催化剂是Pd(0)或Pd(II)催化剂,优选PdCl2、Pd(PPh3)4、Pd(acac)2、PdCl2(CH3CN)2、PdCl2(PCy3)2、PdCl2(PPh3)2、Pd(dppf)Cl2、[(π-ally)PdCl]2、(SIPr)PdCl2(TEA)。任选地,其它膦配体可以与第一钯催化剂一起使用。
钯催化剂与起始原料之比是在0.01-20mol-%的范围内,优选0.01-10mol-%,更优选0.01-5mol-%,最优选0.01-1mol-%。
第一碱可以是有机碱或无机碱。有机碱可以是叔胺诸如Et3N和DIPEA、DABCO、DBU、吡咯烷或哌啶。无机碱可以是K2CO3、Cs2CO3或K3PO4。第一碱与起始原料之比是在1.0-5.0当量的范围内,优选1.0-3.0当量,更优选1.0-3.0当量,最优选1.0-1.5当量。
优选地,该反应在N2气氛下在极性非质子溶剂诸如DMF或DMSO中在80-200℃范围内的温度进行,优选100-180℃,更优选100-150℃,最优选120-150℃。
在步骤B1、B2、B3和B4中的每一个中,通过在10-35℃范围内、优选15-30℃、更优选20-30℃的温度用N-碘琥珀酰亚胺(NIS)作为碘化试剂处理15h,进行三甲基甲硅烷基(TMS)基团向碘化物基团的转化。使用极性非质子溶剂诸如二氯甲烷或氯仿。
在步骤C1、C2、C3和C4中的每一个中,在第二钯催化剂和第二碱的存在下,进行碘化的化合物4*、12*、12b*或14*与作为硼酸衍生物的化合物5*的Suzuki偶联反应。
其中R′是H或具有1-10个碳原子的烷基链或具有3-12个碳原子的环烷基链,或两个残基R′一起代表从频哪醇衍生出的残基。
优选地,硼酸衍生物5*可以是硼酸(R′=-H)或硼酸的酯,例如它的异丙基酯(R′=-CH(CH3)2)、从频哪醇衍生出的酯(R′-R′=-C(CH3)2-C(CH3)2-)。
第二钯催化剂是Pd(0)或Pd(II)催化剂。Pd(0)催化剂可以是四(三苯基膦)钯(0)[Pd(PPh3)4]、三(二亚苄基丙酮)二-钯(0)[Pd2(dba)3]。Pd(II)催化剂可以是二氯双(三苯基膦)-钯(II)[Pd(PPh3)2Cl2]、乙酸钯(II)和三苯基膦或更优选的[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述反应优选地在溶剂如二烷、DMF、DME、THF或异丙醇与水的混合物中和在有第二碱如碳酸氢钠水溶液或K3PO4存在下完成。
在步骤D1和D2中的每一个中,用还原剂处理将硝基(NO2)基团还原成伯胺(NH2)基团。优选地,将Fe或Pd/H2用作还原剂。
在步骤E1、E2、E3和E4中的每一个中,通过与HO-R5或AG-R5的偶联反应引入R5基团。
为了执行偶联反应,首先将HO-R5的羧酸或磺酸基团原位活化以促进与中间体化合物的氨基的偶联反应。如果HO-R5是羧酸,羧酸的活化基团(AG)可以在原位反应中引入。优选地,活化基团(AG)可以选自或包含:卤化物诸如-F、-Br、-Cl、-I、酸酐基团诸如-OCOCH3、N-氧基-苯并三唑基团和N-氧基-琥珀酰亚胺。优选地,HO-R5代表
进一步,通过众所周知的酰胺偶联反应,使HO-R5的羧酸与中间体化合物的胺基团偶联。下述偶联剂中的任一种可以用于酰胺偶联反应:BOP、PyBOP、AOP、PyAOP、TBTU、EEDQ、多磷酸(PPA)、DPPA、HATU、HOBt、HOAt、DCC、EDCI、BOP-Cl、TFFH、Brop、PyBrop和CIP。
为了执行偶联反应,也可以使用具有活化的羧基磺酰基基团的活化的化合物AG-R5。
AG-R5代表
如上所述,活化基团(AG)可以选自或包含:卤化物诸如-F、-Br、-Cl、-I、酸酐基团诸如-OCOCH3、N-氧基-苯并三唑基团和N-氧基-琥珀酰亚胺,优选的AG是Cl。
优选地,AG-R5是
在步骤A3和E4中,保护基(PG)是氨基保护基。胺保护基可以是叔丁基氧基羰基(Boc)或苄氧基羰基(Cbz)并在酸性条件下除去,例如,用HCl或TFA处理。
在一个实施方案中,本发明涉及选自化合物3*、3b*、4*、7*、10*、11*、11b*、12*、12b*、13*、14*和15*的中间体化合物:
TMS是三甲基甲硅烷基。
由下式(IV)表示的本发明化合物的结构-活性关系(SAR)显示出作为细胞有效的突变体选择性的ErbB抑制剂的共价抑制剂。例如通过引入丙烯酸部分(acrylic moiety)获得的共价结合模式对于细胞活性而言至关重要。具有用于共价结合的丙烯酰基部分(acrylmoiety)的本发明实施例与具有丙酸部分(propionic moiety)的相应分子的直接对比表明,共价结合剂具有改善的细胞活性。
表6显示了共价抑制剂(实施例2和148)与对应的可逆类似物(参照物3和4)的对比。在两种情况下,共价抑制剂显示出(实施例2和148)与可逆类似物(参照物3和4)相比改善的细胞活性。
发现本发明的化合物可用于预防和/或治疗具有属于受体的ErbB家族的受体的活化突变的癌症,优选地,所述突变是在EGFR的外显子20内或在HER2的外显子20内的插入。
本发明的其它方面涉及通式(I)的化合物在制备药物组合物中的用途,所述药物组合物可用于预防和/或治疗具有属于受体的ErbB家族的受体的活化突变的癌症,优选地,所述突变是在EGFR的外显子20内或在HER2的外显子20内的插入。
本发明的另一个方面涉及一种治疗方法。该方法包括给遭受癌症的患者施用治疗有效量的至少一种通式(I)的化合物,所述癌症具有属于受体的ErbB家族的受体的活化突变,优选地,所述突变是在EGFR的外显子20内或在HER2的外显子20内的插入
本发明的化合物是EGFR和Her2的突变体、优选如在表3中所示的外显子20突变的选择性抑制剂。
因而,本发明的化合物可用作药物。本发明的化合物可用于预防和/或治疗细胞增殖性疾病,尤其是癌症。
所述癌症选自乳腺癌、结肠癌、前列腺癌、肺癌、胃癌、卵巢癌、子宫内膜癌、肾癌、肝细胞癌、甲状腺癌、子宫癌、食管癌、鳞状细胞癌、白血病、淋巴瘤、骨肉瘤、乳癌(mammacarcinoma)、黑素瘤、胶质母细胞瘤和神经母细胞瘤。
在具体实施方案中,化合物可用于预防和/或治疗非小细胞肺癌(NSCLC)或乳癌。
优选地,所述突变是在EGFR的外显子20内或在HER2的外显子20内的插入。本文中的一个方面是用于预防和/或治疗癌症的本发明的化合物,所述癌症由与EGFR TKI抗性有关的突变造成或与其相关,且尤其由Her2基因或EGFR(Her1)基因的密码子763和775之间的3-21个碱基对(bp)的框架内插入和/或复制造成或与其相关。更优选地,所述突变选自Her2INS8 INS YVMA、EGFR D770_N771insSVD、EGFR H773_V774insNPH、EGFR V769_D770insASV、EGFR P772_H773insPR、EGFR T790M和EGFR T790ML858R。重要序列显示在图1的SEQ-IDNo.1至SEQ:NO 7中。
如表5所示,本发明的化合物对肝微粒体中丙烯酰胺部分的水解具有提高的稳定性。
优选地,下述化合物具有提高的稳定性:
N-(5-(4-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(2-(二甲基氨基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(吗啉代甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(3-吗啉代苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(2-(4-(4-乙酰基哌嗪-1-基)苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-((二甲基氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(吗啉-4-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(3-(二甲基氨基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(4-(乙基磺酰基)哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(3-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(3-(3-(二甲基氨基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(2-(3-((4-乙酰基哌嗪-1-基)甲基)苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(3-(4-乙基哌嗪-1-基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(3-(3-(4-乙基哌嗪-1-基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(3-(吗啉-4-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(3-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(6-吗啉代吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(2-(6-(4-乙酰基哌嗪-1-基)吡啶-3-基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(2-吗啉代吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(2-吗啉代嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(4-乙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-氯-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,1-(6-(4-氯-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(2-(4-(4-乙酰基哌嗪-1-基)苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-((二甲基氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-(4-乙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-(吗啉代甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-(3-(二甲基氨基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,N-(5-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-甲氧基-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(2-(4-(4-乙酰基哌嗪-1-基)苯基)-4-甲氧基-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-甲氧基-2-(4-(吗啉代甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-甲氧基-2-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(4-甲氧基-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(2-甲基-5-(2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺,N-(2-甲基-5-(2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺,N-(2-甲基-5-(2-(2-吗啉代吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺,N-(5-(2-(3-((4-乙酰基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(2-甲基-5-(2-(3-(吗啉代甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺,1-(6-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2H-苯并[b][1,4]嗪-4(3H)-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2H-苯并[b][1,4]嗪-4(3H)-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2H-苯并[b][1,4]嗪-4(3H)-基)丙-2-烯-1-酮,1-(7-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮,1-(7-(4-氯-2-(3-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮,1-(7-(4-氯-2-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮,1-(7-(4-氯-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮,1-(7-(4-氯-2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮,1-(7-(4-氯-2-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮,N-(5-(4-氯-2-(4-(哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,N-(5-(5-氰基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,1-(6-(4-氯-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2H-苯并[b][1,4]嗪-4(3H)-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2H-苯并[b][1,4]嗪-4(3H)-基)丙-2-烯-1-酮,1-(6-(4-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2H-苯并[b][1,4]嗪-4(3H)-基)丙-2-烯-1-酮,1-(6-(4-乙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-乙氧基-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-乙氧基-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-甲氧基-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-甲氧基-2-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-甲氧基-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,1-(6-(4-异丙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-4-甲基苯基)-N-异丙基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺,3-(3-丙烯酰氨基-4-甲基苯基)-N-环己基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸甲酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸乙酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸环丙酯,N-(5-(4-乙氧基-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,N-(5-(5-氯-4-甲基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-乙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(2-(二甲基氨基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-((二甲基氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯,3-(3-丙烯酰氨基-4-甲基苯基)-2-(3-((二甲基氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯。
在一个实施方案中,本发明涉及用于治疗癌症的与至少一种抗癌药物组合的化合物。至少一种抗癌药物是抑制EGFR/HER2酪氨酸激酶的抗癌药物,靶向RAS/RAF/MEK/ERK信号途径的抗癌药物,靶向PI3K/AKT/mTOR信号途径的抗癌药物和/或靶向JAK/STAT信号途径的抗癌药物。
抑制EGFR/HER2酪氨酸激酶的抗癌药物选自A928605、ABT 414、ABT806、AC480、Adgef(吉非替尼)、AEE788、AF802(盐酸阿来替尼)、阿法替尼、Afinitor(依维莫司)、AFM21、AG1478、AGT2000、AL6802、ALL3、AMG595、抗-Cripto-1单克隆抗体PRIMA BIOMED、AP23464、AP26113、ARQ197(tivantinib)、ARRY380、ARRY543(varlitinib甲苯磺酸盐)、ASP7487(linsitinib)、ASP8273、AV203、AVL291、AZD4769、AZD9291、B-Peptimetics ANTYRA、BGB324、BIBW2948BS、双特异性的抗-Her2 Zybodies ZYNGENIA(曲妥珠单抗)、双特异性的抗-Her3 Zybodies ZYNGENIA(西妥昔单抗)、双特异性抗体药物缀合物项目(BispecificAntibody Drug Conjugate Program)AVIDBIOLOGICS、BL7030、BMS536924、BMS582664(丙氨酸布立尼布)、BMS690514、BMSATI2、BT2111(曲妥珠单抗)、CAB051、卡纳替尼(Canertinib)、Caprelsa(凡他尼布)、CCX140、CDX110、CetuGEX、西妥昔单抗AMGEN、西妥昔单抗BIOXPRESSTHERAPEUTICS、西妥昔单抗HARVEST MOON、西妥昔单抗ONCOBIOLOGICS、西妥昔单抗PANACEABIOTECH、西妥昔单抗PLANTFORM、西妥昔单抗ZENOTECH、CGP59326A、Chemofit(吉非替尼)、CI1033(卡纳替尼二盐酸盐)、CIMAher(尼妥珠单抗)、Citoprot-P、CMAB009(西妥昔单抗)、cMet-EGFR双重抑制剂CRYSTALGENOMICS、CO-1686、Cometriq(卡博替尼(cabozantinib))、Conmana(埃克替尼(icotinib)盐酸盐)、CTP15(西妥昔单抗)、CTX023、CUDC101、CYC202(塞利西利(seliciclib))、DC101、DXL1218、EDP13、EGF816、EGFR抗体药物缀合物AVIDBIOLOGICS、EGFR BiTE抗体MICROMET、EGFR单克隆抗体REVO、EGFR Probody药物缀合物CYTOMX、靶向EGFR-抗体的内皮细胞抑制素有效负荷(Endostatin Payload)、EGFR501、EKB569(培利替尼)、EM1-mAb GENMAB、EMD121974(西仑吉肽)、EMD72000(马妥珠单抗)、Emfib(吉非替尼)、表皮生长因子受体(EGFR)人源化抗体CHINA PHARMAHUB、爱必妥(西妥昔单抗)、Erlobenz(厄洛替尼)、Erlocip(厄洛替尼)、Erlonat NATCO(厄洛替尼)、ErlonatRADIANCE(厄洛替尼)、Erlons(盐酸厄洛替尼)、Erlostar(厄洛替尼)、Erloswift(厄洛替尼)、Erlotad(厄洛替尼)、Erlotaz(厄洛替尼)、厄洛替尼CYNO PHARMACEUTICALS(盐酸厄洛替尼)、盐酸厄洛替尼HETERO、盐酸厄洛替尼MYLAN、盐酸厄洛替尼TEVA、厄洛替尼LABORATORIOS INDUQUIMICA、厄洛替尼NAPROD、厄洛替尼P2D BIOSCEINCE、厄洛替尼SALIUS、厄洛替尼SRS PHARMA、厄洛替尼UNITED BIOTECH、Etk/Bmx激酶抑制剂ASTEX、EZN3920、Fderceptin SHANGHAI FUDAN-ZHANGJIANG、FV225、Geffy(吉非替尼)、Geficad(吉非替尼)、吉非替尼CELOGEN、吉非替尼CYNO PHARMACEUTICALS、吉非替尼HETERO、吉非替尼LABORATORIOS INDUQUIMICA、吉非替尼MARKSANS、吉非替尼MISSION VIVACARE、吉非替尼NAPROD、吉非替尼SALIUS、吉非替尼SAVA、吉非替尼SRS PHARMA、吉非替尼UNITED BIOTECH、Gefitoz(吉非替尼)、GefiTrust(吉非替尼)、Gefnib(吉非替尼)、Geftex(吉非替尼)、Geftib(吉非替尼)、Gefticip(吉非替尼)、Geftifos(吉非替尼)、Geftiget(吉非替尼)、Geftin(吉非替尼)、Geftinat NATCO(吉非替尼)、Geftinat RADIANCE(吉非替尼)、Geftistar(吉非替尼)、Genasense(奥利美生钠(oblimersen sodium))、GI3000、Gilotrif(aftinib)、GSK2136773、HC15、HD201(曲妥珠单抗)、HE39、HER-1治疗性癌症疫苗BIOVEN、HER1癌症疫苗、HER2BiTE抗体AMGEN、Herzuma(曲妥珠单抗)、HKI357、HM60390、HM61713、HM78136B(波齐替尼(poziotinib))、HMPL309(西利替尼(theliatinib))、HMPL504(沃利替尼(volitinib))、HMPL813(依吡替尼(epitinib))、HuMax-EGFr(扎芦木单抗)、HyERB(西妥昔单抗)、ICS283、伊马替尼Ecker盐酸盐、Imbruvica(依鲁替尼)、IMC11F8(奈昔木单抗)、IMCA12(西妥木单抗)、IMGN289、INC280、INCB7839(aderbasib)、Inlyta(阿昔替尼)、易瑞沙(吉非替尼)、ISU101(西妥昔单抗)、JNJ26483327、JNJ28871063、JX929、Kabigef(吉非替尼)、KD019、KD020、KHK2866、KRN633、KRN951(替沃扎尼)、KSB102、KT6587、拉帕替尼AQVIDA、二甲苯磺酸拉帕替尼、拉帕替尼SRS PHARMA、Lefibenz(吉非替尼)、Lortinib(厄洛替尼)、LY2875358(伊玛妥珠单抗(emibetuzumab))、MabionEGFR(西妥昔单抗)、MDP01、MDX214(CD89单克隆抗体)、MDX447、Meftinib(吉非替尼)、MEHD7945A、甲萘醌TALON、MGCD265、mir-7模拟物SILENCE、MM121、MM151、MP412、MP470(amuvatinib)、MT062、新的酪氨酸激酶抑制剂MEBIOPHARM、NT004、NT113、ORIL003、ORIL007、OSI632、帕木单抗BIOXPRESS THERAPEUTICS(帕木单抗)、帕木单抗PANPHARMACEUTICALS、PB272(奈拉替尼)、PBI1737、PBI4050、Perjeta(培妥珠单抗)、PF00299804(达克替尼(dacomitinib))、PKI166、PM92102(kahalalide F)、RadioTheraCIM、RAF和HER抑制剂DECIPHERA、RBLX200、RC3095、重糖基化的(Reglycosylated)西妥昔单抗FOUNTAIN BIOPHARM、RG3638(onartuzumab)、RG7160(imgatuzumab)、RX1792、S222611、SAB-Y1 SYNTAB、Sai Pu Ting、SAI-EGFR-ECD MICROMET、SAR103168、SC100、Selatinib Ditosilate QILU、选择性的EGFR抑制剂VICHEM、SL175、SL176、SL433、SL461、SL634、SRXMs MAXOCARE、STIA020X、STIA050X、Stivarga(瑞戈非尼(regorafenib))、STP523、STP801、Stridessa(吉非替尼)、Surrobody药物缀合物SEA LANE、Sym004、Sym013、TaiXinSheng(尼妥珠单抗)、TAK285、特罗凯(盐酸厄洛替尼)、Targretin(贝沙罗汀)、TAS2913、TG03(apricoxib)、TGF治疗性癌症疫苗BIOVEN、TGF-α癌症疫苗MICROMET、曲妥珠单抗ZENOTECH、Trisilensa、三特异性的抗-Her1/Her3 ZybodiesZYNGENIA(西妥昔单抗)、Tykerb(二甲苯磺酸拉帕替尼)、Tyrogef、Tyrokinin 100(盐酸厄洛替尼)、U31287(partitumab)、Ultragef(吉非替尼)、VCC395122、VCC868449、Vectibix(帕木单抗)、VI14442、Xefta(吉非替尼)、YMB1005、Zefotib(吉非替尼)和Zufinib(吉非替尼)。
靶向RAS/RAF/MEK/ERK信号途径的抗癌药物选自:达拉菲尼、GSK2118436、LGX818、威罗菲尼、RAF265、RO5126766、索拉非尼、XL281(Raf抑制剂);ARRY-300、、AZD8330、E6201、PD-0325901、RO4987655、Bimetinib(ARRY-162/MEK162)、Cobimetinib(GDC-0973/XL518)、Refametinib(BAY86-9766/RDEA119)、Pisasertib(AS703026)、司美替尼(AZD6244/ARRY-142886)、TAK-733、曲美替尼(GSK1120212)(MEK抑制剂)、BVD-523和MK8553(ERK抑制剂)。
靶向PI3K/AKT/mTOR信号途径的抗癌药物选自:BGT226、BEZ235、GDC-0980、GSK2126458、PF-04691502、PF-05212384/PKI-587、SF1126、XL765/SAR245409、BKM120、BYL719、CAL-101、GDC-0032、GDC-0941、GSK2636771、IPI-145、NVP-BEZ235、PX866、XL147(PI3K抑制剂);芥酸磷酸胆碱(Erucylphosphocholine)、GSK2141795、GSK690693、米替福新、MK2206、PBI-05204、哌立福新、RX-0201、SR13668和XL-418(AKT抑制剂);AZD2014、AZD8055、CC-223、依维莫司(RAD001)、地磷莫司(Ridaforolimus)(MK-8669)、OSI-027、西罗莫司(雷帕霉素)、Temsirolmus(CCI-779)(mTOR抑制剂)。
靶向JAK/STAT信号途径的抗癌药物是JAK激酶抑制剂或STAT抑制剂。JAK激酶抑制剂对JAK1、JAK2和/或JAK3具有抑制活性且选自ABT-494、AT9283、二盐酸阿替莫德、AZD1480、Baricitinib、BMS-911543、CP690550、葫芦素I、Decernotinib、Fil gotinib、Gandotinib、GSK2586184、Itacitinib(INCB039110)、INCB018424、INCB047986、INCB052793、来妥替尼(Lestaurtinib)、Momelotinib(CYT387)、NS-018、NSC33994、Pacritinib、Peficitinib、鲁索替尼(Jakafi)、PF-04965842、SD 1008、托法替尼、Upadacitinib、XL019和WP1066。
STAT抑制剂对STAT 1、2、3、4、5a、5b和6、尤其STAT3和STAT5b具有抑制活性且选自AZD9150、辣椒素、CPA-1、CPA-7、FLLL11、FLLL12、FLLL32、FLLL62、IS3295、JQ1、OPB-111077、OPB-31121、OPB-51602和匹莫齐特。
药物组合物
根据本发明的药物组合物包含作为活性成分的至少一种根据本发明的化合物以及至少一种药学上可接受的(即无毒的)载体、赋形剂和/或稀释剂。本发明的药物组合物可以以已知的方式在常规的固体或液体载体或稀释剂和常规的药学上制备的辅助剂中以合适的剂量水平制备。优选的制剂适合用于口服。这些施用形式包括、例如丸剂、片剂、薄膜片剂、包衣片剂、胶囊、粉剂和蓄池(deposits)。
任选地,根据本发明的药物组合物进一步包含至少一种抗癌药物。所述至少一种抗癌药物是如上定义的抑制EGFR/HER2酪氨酸激酶的抗癌药物、靶向RAS/RAF/MEK/ERK信号途径的抗癌药物、靶向PI3K/AKT/mTOR信号途径的抗癌药物和/或靶向JAK/STAT信号途径的抗癌药物。
此外,本发明还包括用于胃肠外施用的药物制备物(preparation),包括真皮、真皮内(intradermal)、胃内、皮内(intracutaneous)、血管内、静脉内、肌肉内、腹膜内、鼻内、阴道内、颊内、经皮、直肠、皮下、舌下、局部或透皮施用,除了典型的媒介物和/或稀释剂以外,所述制剂还含有至少一种根据本发明的化合物和/或其药学上可接受的盐作为活性成分。
含有至少一种根据本发明的化合物和/或其药学上可接受的盐作为活性成分的根据本发明的药物组合物通常将与合适的载体材料一起施用,所述载体材料针对预期的施用形式进行选择,即用于以片剂、胶囊(固体填充、半固体填充或液体填充)、构造用粉剂、凝胶、酏剂、可分散颗粒、糖浆剂、混悬剂等的形式口服施用,且符合常规的药学实践。例如,对于以片剂或胶囊的形式口服施用而言,可以将活性药物组分与任何口服无毒的药学上可接受的载体组合,优选与惰性载体如乳糖、淀粉、蔗糖、纤维素、硬脂酸镁、磷酸二钙、硫酸钙、滑石、甘露醇、乙醇(液体填充的胶囊)等组合。此外,合适的粘合剂、润滑剂、崩解剂和着色剂也可以掺入片剂或胶囊中。粉剂和片剂可以含有约5至约95-重量%的根据通式(I)的衍生物或其类似物化合物或各种药学上有活性的盐作为活性成分。
适宜的粘合剂包括淀粉、明胶、天然糖类、玉米甜味剂、天然胶和合成胶,诸如阿拉伯胶、海藻酸钠、羟甲基纤维素、聚乙二醇和蜡。在合适的润滑剂中,可以提及硼酸、苯甲酸钠、醋酸钠、氯化钠等。合适的崩解剂包括淀粉、甲基纤维素、瓜尔胶等。在适当的情况下,也可以包括甜味剂和矫味剂以及防腐剂。在下面更详细地讨论崩解剂、稀释剂、润滑剂、粘合剂等。
此外,本发明的药物组合物可以配制成持续释放形式,以提供任何一种或多种组分或活性成分的速率控制释放,以优化治疗效果,例如抗癌活性或对癌症转移灶(cancermetastases)等的活性。用于持续释放的合适剂型包括具有不同崩解速率或控释的层的片剂,浸渍有活性组分并成形为片剂形式的聚合物基质或者含有这样的被浸渍或被包封过的多孔聚合物基质的胶囊。
液体形式制备物包括溶液、混悬剂和乳剂。作为一个例子,可以提及用于胃肠外注射的水或水/丙二醇溶液,或用于口服溶液、混悬剂和乳剂的甜味剂和遮光剂的添加。液体形式制备物还可包括用于鼻内施用的溶液。
适用于吸入的气雾剂制备物可以包括溶液和粉末形式的固体,它们可以与药学上可接受的载体(诸如惰性的压缩气体,例如氮气)组合存在。
为了制备栓剂,首先将低熔点蜡(诸如脂肪酸甘油酯如可可脂的混合物)熔化,并然后将活性成分均匀地分散在其中,例如通过搅拌。然后将熔化的均匀混合物倒入尺寸合适的模具中,使其冷却,并由此固化。
还包括固体形式制备物,其意图在使用前不久转变成用于口服或胃肠外施用的液体形式制剂。这样的液体形式包括溶液、混悬剂和乳剂。
也可以透皮递送根据本发明的化合物。透皮组合物可以具有乳膏剂、洗剂、气雾剂和/或乳剂的形式,并且可以被包含在本领域已知用于此目的的基质或贮库(reservoir)类型的透皮贴剂中。
如本文所述的术语“胶囊”表示用于保持或容纳包含活性成分的组合物的特定容器或外壳,其例如由甲基纤维素、聚乙烯醇或变性明胶或淀粉制成。具有硬壳的胶囊通常由来自骨头或猪皮的相对高凝胶强度的明胶的掺合物制成。胶囊本身可以含有少量的染料、遮光剂、增塑剂和/或防腐剂。
在片剂下,应理解为压制或模制的固体剂型,其包含活性成分和合适的稀释剂。可以如下制备片剂:通过压缩混合物或颗粒,其通过湿法制粒、干法制粒或通过本领域普通技术人员众所周知的压缩获得。
口服凝胶表示分散或溶解在亲水性半固体基质中的活性成分。
构造用粉剂表示含有活性成分和合适的稀释剂的粉末掺合物,所述稀释剂可以悬浮例如在水中或在汁液(juice)中。
合适的稀释剂是通常构成组合物或剂型的主要部分的物质。合适的稀释剂包括糖诸如乳糖、蔗糖、甘露醇和山梨醇,从小麦、玉米、大米和马铃薯衍生出的淀粉,和纤维素诸如微晶纤维素。组合物中的稀释剂的量可以为总组合物的约5至约95重量%,优选约25至约75重量%,且更优选约30至约60重量%。
术语崩解剂表示添加到组合物中以支持分解(崩解)和释放药物的药学活性成分的材料。合适的崩解剂包括淀粉、“冷水溶性的”变性淀粉诸如羧甲基淀粉钠、天然的和合成的树胶诸如刺槐豆胶、刺梧桐树胶、瓜尔胶、黄蓍胶和琼脂、纤维素衍生物诸如甲基纤维素和羧甲纤维素钠、微晶纤维素和交联的微晶纤维素诸如交联羧甲基纤维素钠(sodiumcroscaramellose)、海藻酸盐诸如海藻酸和海藻酸钠、粘土诸如皂粘土和泡腾剂混合物。组合物中崩解剂的量可以为组合物的约2至约20重量%,更优选约5至约10重量%。
粘合剂是将粉末颗粒粘合或“胶合”在一起并通过形成颗粒使其具有粘性的物质,因此在制剂中用作“粘合剂”。粘合剂会增加在稀释剂或填充剂中已有的粘合强度。合适的粘合剂包括糖诸如蔗糖,衍生自小麦、玉米、大米和马铃薯的淀粉,天然树胶诸如阿拉伯胶、明胶和黄蓍胶,海藻衍生物诸如海藻酸、海藻酸钠和藻酸铵钙(ammonium calciumalginate),纤维素材料诸如甲基纤维素、羧甲纤维素钠和羟丙基甲基纤维素,聚乙烯吡咯烷酮,和无机化合物诸如硅酸镁铝。在组合物中的粘合剂的量可以为组合物的约2至约20重量%,优选约3至约10重量%,且更优选约3至约6重量%。
润滑剂表示被添加到剂型中以使片剂颗粒等在被压缩以后通过减少摩擦或磨损而从模具中释放的一类物质。合适的润滑剂包括金属硬脂酸盐诸如硬脂酸镁、硬脂酸钙或硬脂酸钾、硬脂酸、高熔点蜡、以及其它水溶性的润滑剂诸如氯化钠、苯甲酸钠、醋酸钠、油酸钠、聚乙二醇和D,L-亮氨酸。润滑剂通常在压缩前的最后一步添加,因为它们必须存在于颗粒表面。组合物中润滑剂的量可以为组合物的约0.2至约5重量%,优选为组合物的约0.5至约2重量%,并且更优选为约0.3至约1.5重量%。
助流剂(glident)是防止药物组合物的组分结块并改善颗粒的流动特性从而使流动平滑和均匀的材料。合适的助流剂包括二氧化硅和滑石。组合物中助流剂的量可以为最终组合物的约0.1至约5重量%,优选约0.5至约2重量%。
着色剂是使组合物或剂型着色的赋形剂。这样的赋形剂可以包括吸附在合适的吸附剂如粘土或氧化铝上的食品级染料。着色剂的量可为组合物的约0.1至约5重量%,优选约0.1-1重量%。
本发明的化合物适用于医学,特别是人医学,但是也适用于兽医学。化合物的剂量可以由熟练的从业人员根据要治疗的障碍的类型和严重程度来确定。
本发明的化合物可以作为单一疗法施用,或与其它活性剂、特别是化学治疗剂或抗肿瘤抗体一起施用。此外,它们可以与外科手术和/或辐照联合使用。
附图描述
图1:EGFR突变体EGFR D770_N771insSVD、EGFR H773_V774insNPH、EGFR V769_D770insASV、EGFR P772_H773insPR、EGFR T790M和EGFR T790ML858R和HER突变体Her2INS8 INS YVMA的核心序列。
图2显示了50分钟以后在肝微粒体存在下参照物1的丙烯酰胺部分的水解。
化合物的制备:
一般信息:
所有涉及对空气或湿气敏感的试剂或中间体的反应均在氩气氛下在火焰干燥的玻璃器皿中进行。干燥的溶剂(THF、甲苯、MeOH、DMF、DCM)作为市售品使用。在BrukerDRX400(400MHz)上记录1H-NMR和13C-NMR。多重性表示为:br s(加宽的单峰)、s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、quin(五重峰)、m(多重峰);且以赫兹(Hz)为单位给出偶合常数(J)。使用配备SQ 3100质量检测器波谱仪的Waters Acquity Performance LiquidChromatography(UPLC)得到HPLC-电喷射质谱图(HPLC ES-MS)。柱:Acquity UPLC BEHC181.7um,2.1x50mm。流速:0.5ml/min。洗脱液:A:含有0.05%甲酸的H2O,和B:含有0.05%TFA的ACN。所有化学物质和溶剂购自商业来源如Sigma-Aldrich、Fluka、TCI、AcrosOrganics、ABCR、Alfa Aesar、Enamine、VWR、Combi-Blocks、Apollo Scientific、AquillaPharmatech、Ark Pharm、D-L Chiral Chemicals、ChemBridge、Renno Tech、Accela、KeyOrganics、Pharmablock和Chem Impex。除非另外指出,否则所有商购可得的化合物不经进一步纯化以接收状态使用。
在化学物质的描述中和在实施例中使用的缩写如下:
ACN(乙腈);br(宽的);CDCl3(氘代氯仿);cHex(环己烷);DCM(二氯甲烷);DIPEA(二异丙基乙胺);DMF(二甲基甲酰胺);DMSO(二甲亚砜);eq.(当量);ES(电喷射);EtOAc(乙酸乙酯);EtOH(乙醇);HATU(O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐);HCl(盐酸);HOAc(乙酸);H2O(水);K2CO3(碳酸钾);KOH(氢氧化钾);MeOH(甲醇);MS(质谱法);Mwt(分子量);NaHCO3(碳酸氢钠);NH3(氨);NH4Cl(氯化铵);NIS(N-碘琥珀酰亚胺);NMP(N-甲基-2-吡咯烷酮(pyrrolidon));NMR(核磁共振);Pd(dppf)Cl2([1,1’-双(二苯基膦基)二茂铁]二氯钯(II)与二氯甲烷的复合物);iPrOH(异丙醇);PyBroP(三吡咯烷基溴化鏻六氟磷酸盐);RP(反相);RT(室温);sat.aq.(饱和水溶液);SiO2(硅胶);TFA(三氟乙酸);THF(四氢呋喃)。
制备实施例
实施例1:
N-(5-(4-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(trifluoroacetate)(A1)
步骤1:4-氯-3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]
吡啶(A1)
在N2气氛下将在无水(dry)DMF(40mL)中的4-氯-3-碘吡啶-2-胺(5.0g,19.0mmol,1.0当量)、三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷(5.7g,25.0mmol,1.25当量)、1,4-二氮杂双环[2.2.2]辛烷(3.6g,32.3mmol,1.7当量)和二氯双(三苯基膦)钯(II)(1.4g,2.0mmol,0.1当量)分入三个微波瓶中。将每个瓶在微波中在145℃加热2h。加入EtOAc(250mL)并将有机相用饱和NaHCO3水溶液洗涤3次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至1:1)纯化以产生作为米色固体的期望产物A1(3.9g,10.8mmol,57%)。1H NMR(400MHz,d6-DMSO,300K)δ0.11(s,9H),2.58(s,3H),7.12(d,J=5.0Hz,1H),7.52(d,J=7.9Hz,1H),7.63(d,J=7.9Hz,1H),7.91(s,1H),8.21(d,J=5.0Hz,1H),12.04(s,1H)。MS(ES)C17H18ClN3O2Si要求(requires):359,实测(found):360(M+H)+。
步骤2:5-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯
胺(A2)
将4-氯-3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶A1(5.6g,15.56mmol,1.0当量)和铁(4.3g,77.8mmol,5当量)在EtOH(100mL)和饱和NH4Cl水溶液(10mL)中的溶液在80℃搅拌5h。将溶液穿过垫过滤。在真空中除去溶剂。将粗制物溶解在EtOAc中并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至0:100)纯化以产生作为米色固体的期望产物A2(5.0g,15.2mmol,97%)。1H NMR(400MHz,d6-DMSO,300K)δ0.10(s,9H),2.10(s,3H),4.76(br s,2H),6.44(d,J=7.4Hz,1H),6.60(s,1H),6.89(d,J=7.4Hz,1H),7.04(d,J=5.1Hz,1H),8.15(d,J=5.1Hz,1H),11.71(s,1H)。MS(ES)C17H20ClN3Si要求:329,实测:330(M+H)+。
步骤3:N-(5-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基
苯基)丙烯酰胺(A3)
通过规程A或规程B制备A3:
规程A:
在0℃向A2(2760mg,8.4mmol,1.0当量)和DIPEA(14.6mL,84.0mmol,10.0当量)在无水DCM(100mL)中的溶液中缓慢地加入在无水DCM(5mL)中的丙烯酰氯(acrylolylchloride)(757mg,8.4mmol,1.0当量)。将混合物搅拌5min。将溶液用EtOAc稀释并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至1:1)纯化以产生作为白色固体的期望产物A3(3070mg,8.0mmol,95%)。1H NMR(400MHz,d6-DMSO,300K)δ0.11(s,9H),2.28(s,3H),5.72(dd,J=2.1Hz,J=10.2Hz,1H),6.22(dd,J=2.1Hz,J=16.9Hz,1H),6.55(dd,J=10.2Hz,J=16.9Hz,1H),7.07(m,2H),7.22(d,J=7.7Hz,1H),7.56(s,1H),8.17(d,J=5.0Hz,1H),9.42(s,1H),11.83(s,1H)。MS(ES)C20H22ClN3OSi要求:383,实测:384(M+H)+。
规程B:
在0℃向HATU(3460mg,9.1mmol,1.5当量)在DMF(10mL)中的溶液中加入丙烯酸(655mg,9.1mmol,1.5当量)和DIPEA(1548mg,9.1mmol,2.0当量)。将混合物搅拌15min。然后加入A2(2000mg,6.0mmol,1.0当量)并将混合物在0℃搅拌4h。将溶液用EtOAc稀释并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至1:1)纯化以产生作为白色固体的期望产物A3(890mg,2.3mmol,39%)。MS(ES)C20H22ClN3OSi要求:383,实测:384(M+H)+。
步骤4:N-(5-(4-氯-2-碘-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺
(A4)
将N-(5-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺A3(890mg,2.32mmol,1.0当量)和N-碘琥珀酰亚胺(937mg,4.18mmol,1.8当量)溶解在无水二氯甲烷(300mL)中并在室温搅拌15h。将有机相用饱和Na2S2O3水溶液洗涤1次和用饱和NaHCO3水溶液洗涤3次。将有机相经Na2SO4干燥并在真空中除去溶剂,产生作为黄色固体的期望产物A4(970mg,2.21mmol,95%)。将粗制物不经纯化用在下一步中。MS(ES)C17H13ClIN3O要求:437,实测:438(M+H)+。
步骤5:N-(5-(4-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡
啶-3-基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(A5)
将N-(5-(4-氯-2-碘-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯基-酰胺A4(40mg,0.09mmol,1.0当量)、{4-[(4-甲基哌嗪-1-基)甲基]苯基}硼酸二盐酸盐(32mg,0.14mmol,1.5当量)和K3PO4(38mg,0.18mmol,2.0当量)在二烷/H2O(3mL/0.6mL)中的混合物用N2气流脱气5min。加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷加成化合物(8mg,0.01mmol,0.1当量)并将反应混合物在微波炉中加热至130℃保持2h。将反应混合物用EtOAc稀释,用饱和NaHCO3水溶液洗涤3次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物A5(5mg,0.01mmol,8%)。1HNMR(400MHz,CDCl3,300K)δ12.45(s,1H),9.44(s,1H),8.16(dd,J=1.3Hz,J=5.2Hz,1H),7.52(s,1H),7.44(d,J=7.9Hz,2H),7.25(d,J=7.9Hz,2H),7.20(d,J=7.8Hz,1H),7.10(dd,J=1.3Hz,J=5.2Hz,1H),7.04(d,J=7.8Hz,1H),6.51(dd,J=10.1Hz,J=17.1Hz,1H),6.17(d,J=17.1Hz,1H),5.70(d,J=10.1Hz,1H),3.58(s,2H),3.01-2.89(m,4H),2.74(s,3H),2.65(m,2H),2.31(m,2H),2.25(s,3H)。MS(ES)C29H30ClN5O要求:500,实测:501(M+H)+。
根据关于A5(实施例1)描述的规程制备下表中的实施例。
实施例44:
N-(5-(4-氯-2-(3-(4-甲基哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-
2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(B2)
步骤1:3-(3-(3-丙烯酰氨基-4-甲基苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-2-基)
苯甲酸(B1)
将N-(5-(4-氯-2-碘-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺A4(500mg,1.14mmol,1.0当量)、3-羧基苯基硼酸(284mg,1.71mmol,1.5当量)和K3PO4(483mg,2.28mmol,2.0当量)在二烷/H2O(15mL/3mL)中的混合物用N2气流脱气5min。加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷加成化合物(93mg,0.11mmol,0.1当量)并将反应混合物在微波炉中加热至130℃保持2h。除去溶剂,并将粗制物通过硅胶上的快速色谱法(DCM/MeOH=100:0至0:100)纯化以产生作为米色固体的期望产物B1(200mg,0.46mmol,41%)。MS(ES)C24H18ClN3O3要求:431,实测:432(M+H)+。
步骤2:N-(5-(4-氯-2-(3-(4-甲基哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-
3-基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(B2)
在0℃向B1(10mg,0.02mmol,1.0当量)和HATU(18mg,0.05mmol,2.0当量)在DMF(2mL)中的溶液中加入1-甲基哌嗪(4mg,0.03mmol,1.5当量)和DIPEA(20uL,0.11mmol,5.0当量)。将混合物搅拌1h。将反应混合物用EtOAc稀释,用饱和NaHCO3水溶液洗涤3次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物B2(3mg,0.003mmol,14%)。1H NMR(400MHz,MeOD,300K)δ8.17(d,J=5.3Hz,1H),7.77(d,J=7.9Hz,1H),7.57(t,J=7.7Hz,1H),7.46(d,J=7.7Hz,1H),7.40(m,2H),7.25(d,J=7.7Hz,1H),7.12(m,2H),6.50(dd,J=10.2Hz,J=17.0Hz,1H),6.35(d,J=17.0Hz,1H),5.80(d,J=10.2Hz,1H),3.54-2.80(m,8H),2.95(s,3H),2.32(s,3H)。MS(ES)C29H28ClN5O2要求:513,实测:514(M+H)+。
根据关于B2(实施例44)描述的规程制备下表中的实施例。
实施例55:
1-(6-(4-氯-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚
啉-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(C5)
步骤1:6-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-
甲酸叔丁酯(C1)
按照在制备实施例1步骤1中报告的一般规程,从4-氯-3-碘吡啶-2-胺和6-((三甲基甲硅烷基)乙炔基)吲哚啉-1-甲酸叔丁酯制备C1(1.0g,2.26mmol,76%,米色固体)。MS(ES)C23H28ClN3O2Si要求:441,实测:442(M+H)+。
步骤2:4-氯-3-(吲哚啉-6-基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶
(C2)
在室温将在30%的TFA于DCM中的溶液(60mL)中的6-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-甲酸叔丁酯C1(1.0g,2.26mmol)搅拌2h。蒸发溶剂产生作为米色固体的期望产物C2,其不经纯化用于下一步。MS(ES)C18H20ClN3Si要求:341,实测:342(M+H)+。
步骤3:1-(6-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-
1-基)丙-2-烯-1-酮(C3)
按照在制备实施例1步骤3规程A中报告的一般规程,从C2制备C3(50mg,0.13mmol,6%,米色固体)。MS(ES)C21H22ClN3OSi要求:395,实测:396(M+H)+。
步骤4:1-(6-(4-氯-2-碘-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-
1-酮(C4)
按照在制备实施例1步骤4中报告的一般规程,从C3制备C4(51mg,0.11mmol,84%,黄色固体)。MS(ES)C18H13ClIN3O要求:448,实测:449(M+H)+。
步骤5:1-(6-(4-氯-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)吲哚啉-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(C5)
按照在制备实施例1步骤5中报告的一般规程,从C4制备C5。将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物C5(10mg,0.01mmol,12%)。1H NMR(400MHz,d4-MeOD,300K)δ1.92(m,3H),2.10(d,J=13.6Hz,2H),2.85(m,1H),2.91(s,3H),3.15(m,3H),3.59(d,J=10.3Hz,2H),4.31(t,J=8.5Hz,2H),5.82(d,J=10.6Hz,1H),6.33(d,J=16.8Hz,1H),6.76(dd,J=10.6Hz,J=16.8Hz,1H),7.05(d,J=7.7Hz,1H),7.10(d,J=5.2Hz,1H),7.30-7.19(m,3H),7.46(d,J=8.1Hz,2H),7.71(d,J=8.1Hz,1H),8.12(d,J=5.2Hz,1H),8.25(s,1H)。MS(ES)C30H29ClN4O要求:496,实测:497(M+H)+。
根据关于C5(实施例55)描述的规程制备下表中的实施例。
实施例72
N-(5-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(D5)
步骤1:4-甲氧基-3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,
3-b]吡啶(D1)
按照在制备实施例1步骤1中报告的一般规程,从3-碘-4-甲氧基吡啶-2-胺和三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷制备D1(3.50g,9.86mmol,38%,米色固体)。MS(ES)C18H21N3O3Si要求:355,实测:356(M+H)+。
步骤2:5-(4-甲氧基-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲
基苯胺(D2)
将D1(2.5g,7mmol,1当量)和铁(1.9g,35mmol,5当量)在EtOH(100mL)和饱和NH4Cl水溶液(10mL)中的溶液在80℃搅拌5h。将溶液穿过垫过滤。在真空中除去溶剂。将粗制物溶解在EtOAc中并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至0:100)纯化以产生作为米色固体的期望产物D2(1.0g,3.1mmol,44%)。MS(ES)C18H23N3OSi要求:325,实测:326(M+H)+。
步骤3:N-(5-(4-甲氧基-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-
甲基苯基)丙烯酰胺(D3)
按照在制备实施例1步骤3规程A中报告的一般规程,从D2制备D3(712mg,1.87mmol,40%,白色固体)。MS(ES)C21H25N3O2Si要求:379,实测:380(M+H)+。
步骤4:N-(5-(2-碘-4-甲氧基-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯
酰胺(D4)
按照在制备实施例1步骤4中报告的一般规程,从D3制备D4(512mg,1.18mmol,66%,黄色固体)。MS(ES)C18H16IN3O2要求:433,实测:434(M+H)+。
步骤5:N-(5-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡
啶-3-基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(D5)
按照在制备实施例1步骤5中报告的一般规程,从D4制备D5。将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物D5(2mg,0.01mmol,3%)。1H NMR(400MHz,d4-MeOD,300K)δ2.30(s,3H),2.96(s,3H),3.08(m,2H),3.26(m,2H),3.57(m,2H),3.91(m,2H),3.98(s,3H),5.78(dd,J=10.2Hz,J=1.5Hz,1H),6.34(dd,J=17.0Hz,J=1.5Hz,1H),6.51(dd,J=10.2Hz,J=17.0Hz,1H),6.99(d,J=8.8Hz,2H),7.03(d,J=6.7Hz,1H),7.08(d,J=8.1Hz,1H),7.19(d,J=7.8Hz,1H),7.38(d,J=8.8Hz,2H),7.46(s,1H),8.22(d,J=7.6Hz,1H)。MS(ES)C29H31N5O2要求:481,实测:482(M+H)+。
根据关于D5(实施例72)描述的规程制备下表中的实施例。
实施例78:
N-(2-甲基-5-(2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-
基)苯基)丙烯酰胺2,2,2-三氟乙酸盐(E1)
步骤1:3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶
(E1)
在N2气氛下将在无水DMF(40mL)中的2-氨基-3-碘吡啶(5.65g,25.71mmol,1.2当量)、三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷(5.00g,21.43mmol,1.0当量)、1,4-二氮杂双环[2.2.2]辛烷(4.08g,32.3mmol,1.7当量)和二氯双(三苯基膦)钯(II)(1.51g,2.14mmol,0.1当量)分入三个微波瓶中。将每个瓶在微波中在145℃加热2h。加入EtOAc(250mL)并将有机相用饱和NaHCO3水溶液洗涤3次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(DCM/MeOH=100:0至10:1)纯化以产生作为橙色固体的期望产物E1(4.96g,10.25mmol,71%)。MS(ES)C17H19N3O2Si要求:325,实测:326(M+H)+。
步骤2:2-甲基-5-(2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)苯胺(E2)
将3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶E1(4.96g,15.24mmol,1.0当量)和铁(8.51g,152.4mmol,10当量)在EtOH(100mL)和饱和NH4Cl水溶液(20mL)中的溶液在80℃搅拌15h。将溶液穿过垫过滤。在真空中除去溶剂。将粗制物溶解在EtOAc中并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物(3.04g,10.3mmol,68%,橙色固体)不经进一步纯化地用在下一步中。MS(ES)C17H21N3Si要求:295,实测:296(M+H)+。
步骤3:N-(2-甲基-5-(2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)
丙烯酰胺(E3)
在0℃向E2(1000mg,3.38mmol,1.0当量)和DIPEA(2.96mL,16.92mmol,5.0当量)在无水DCM(100mL)中的溶液中缓慢地加入在无水DCM(5mL)中的丙烯酰氯(306mg,3.38mmol,1.0当量)。将混合物搅拌30min。将溶液用EtOAc稀释并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至1:2)纯化以产生作为白色固体的期望产物E3(498mg,1.43mmol,42%)。MS(ES)C20H23N3OSi要求:349,实测:350(M+H)+。
步骤4:N-(5-(2-碘-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺(E4)
将N-(2-甲基-5-(2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺E3(497mg,1.42mmol,1.0当量)和N-碘琥珀酰亚胺(576mg,2.56mmol,1.8当量)溶解在无水二氯甲烷(100mL)中并在室温搅拌15h。将有机相用饱和Na2S2O3水溶液洗涤1次和用饱和NaHCO3水溶液洗涤3次。将有机相经Na2SO4干燥并在真空中除去溶剂,产生作为黄色固体的期望产物E4(337mg,0.84mmol,59%)。将粗制物不经纯化用在下一步中。MS(ES)C17H14IN3O要求:403,实测:404(M+H)+。
步骤5:N-(2-甲基-5-(2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]
吡啶-3-基)苯基)丙烯酰胺2,2,2-三氟乙酸盐(E5)
将N-(5-(2-碘-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺E4(50mg,0.12mmol,1.0当量)、2-(4-甲基哌嗪子基(piperazino))吡啶-5-硼酸频哪醇酯(49mg,0.16mmol,1.3当量)和K3PO4(53mg,0.24mmol,2.0当量)在二烷/H2O(3mL/0.6mL)中的混合物用N2气流脱气5min。加入[1,1'-双(二苯基膦基)-二茂铁]二氯化钯二氯甲烷加成化合物(10mg,0.01mmol,0.1当量)并将反应混合物在微波炉中加热至110℃保持1h。将粗制的溶液通过反相RP-HPLC(柱:C18)直接纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物E5(22mg,0.03mmol,23%)。1HNMR(400MHz,d6-DMSO,300K)δ2.27(s,3H),2.85(s,3H),3.12(m,4H),3.51(d,J=11.3Hz,2H),4.46(d,J=12.3Hz,2H),5.76(d,J=10.3Hz,1H),6.24(d,J=17.0Hz,1H),6.57(dd,J=10.3Hz,J=17.0Hz,1H),6.99(m,2H),7.12(dd,J=4.7Hz,J=7.9Hz,1H),7.24(d,J=7.9Hz,1H),7.67(s,1H),7.72(dd,J=2.4Hz,J=8.7Hz,1H),7.89(d,J=7.9Hz,1H),8.26(d,J=4.7Hz,1H),8.33(d,J=2.4Hz,1H),9.51(s,1H),12.14(s,1H)。MS(ES)C27H28N6O要求:452,实测:453(M+H)+。
根据关于E5(实施例78)描述的规程制备下表中的实施例。
实施例83:
1-(6-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2H-
苯并[b][1,4]
嗪-4(3H)-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(F4)
按照在制备实施例1步骤1中报告的一般规程,从4-氯-3-碘吡啶-2-胺(867mg,3.41mmol,1.0当量)和6-((三甲基甲硅烷基)乙炔基)-2H-苯并[b][1,4]嗪-4(3H)-甲酸叔丁酯(1.131mg,3.41mmol,1.0当量)制备F1(632mg,1.37mmol,40%,米色固体)。MS(ES)C23H28ClN3O3Si要求:458,实测:459(M+H)+。
将6-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-2H-苯并[b][1,4]嗪-4(3H)-甲酸叔丁酯F1(300mg,0.65mmol)和N-碘琥珀酰亚胺(264mg,1.17mmol,1.8当量)溶解在无水二氯甲烷(100mL)中并在室温搅拌5h。将有机相用饱和Na2S2O3水溶液洗涤1次和用饱和NaHCO3水溶液洗涤3次。将有机相经Na2SO4干燥并在真空中除去溶剂,产生作为棕色固体的期望产物F2(341mg,0.65mmol,100%)。将粗制物不经纯化用在下一步中。MS(ES)C20H19ClIN3O3要求:511,实测:512(M+H)+。
将6-(4-氯-2-碘-1H-吡咯并[2,3-b]吡啶-3-基)-2H-苯并[b][1,4]嗪-4(3H)-甲酸叔丁酯F2(341mg,0.65mmol,1.0当量)、4-(4-甲基哌嗪-1-基)苯基硼酸(186mg,0.85mmol,1.3当量)和K3PO4(275mg,1.30mmol,2.0当量)在二烷/H2O(10mL/1mL)中的混合物用N2气流脱气5min。加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷加成化合物(53mg,0.06mmol,0.1当量)并将反应混合物在微波炉中加热至130℃保持2h。将反应混合物用EtOAc稀释,用饱和NaHCO3水溶液洗涤3次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗制物溶解在30%的TFA于DCM中的溶液(60mL)中并在室温搅拌2h。在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(DCM/含有0.1%NEt3的MeOH=100:0至5:1)纯化以产生作为白色固体的期望产物F3(145mg,0.31mmol,49%)。MS(ES)C26H26ClN5O要求:459,实测:460(M+H)+。
步骤4:1-(6-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2H-苯并[b][1,4]
嗪-4(3H)-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(F4)
在0℃向F3(29mg,0.063mmol,1.0当量)和DIPEA(110uL,0.63mmol,10.0当量)在无水DCM(4mL)中的溶液中缓慢地加入在无水DCM(5mL)中的丙烯酰氯(acrylolyl chloride)(5.1mg,0.057mmol,0.9当量)。将混合物搅拌5min。将溶液用EtOAc稀释并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗制的溶液通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物F4(24mg,0.03mmol,51%)。1H NMR(400MHz,d4-MeOH,300K)δ2.96(s,3H),3.06(m,2H),3.25(m,4H),3.59(m,2H),3.92(m,2H),4.34(m,2H),5.38(d,J=10.4Hz,1H),6.16(dd,J=2.0Hz,J=16.8Hz,1H),6.36(m,1H),6.98(d,J=8.3Hz,1H),7.02(d,J=8.9Hz,2H),7.12(d,J=5.4Hz,1H),7.22(d,J=8.3Hz,1H),7.37(d,J=8.9Hz,2H),8.10(d,J=5.4Hz,1H)。MS(ES)C23H28ClN3O3Si要求:513,实测:514(M+H)+。
根据关于F4(实施例83)描述的规程制备下表中的实施例。
实施例86:
1-(7-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,
4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(G5)
步骤1:7-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢
喹啉-1(2H)-甲酸叔丁酯(G1)
在N2气氛下将在无水DMF(30mL)中的4-氯-3-碘吡啶-2-胺(1175mg,4.6mmol,1.0当量)、7-((三甲基甲硅烷基)乙炔基)-3,4-二氢喹啉-1(2H)-甲酸叔丁酯(1522mg,4.6mmol,1.0当量)、1,4-二氮杂双环[2.2.2]辛烷(876mg,7.8mmol,1.7当量)和二氯双(三苯基膦)钯(II)(351mg,0.4mmol,0.1当量)分入三个微波瓶中。将每个瓶在微波中在145℃加热2h。在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至1:1)纯化以产生作为米色固体的期望产物G1(1010mg,2.2mmol,48%)。1H NMR(400MHz,d6-DMSO,300K)δ0.09(s,9H),1.39(s,9H),1.87(m,2H),2.79(7,J=6.5Hz,2H),3.65(m,2H),6.94(dd,J=1.7Hz,J=7.7Hz,1H),7.06(d,J=5.1Hz,1H),7.09(d,J=7.7Hz,1H),7.61(d,J=1.7Hz,1H),8.17(d,J=5.1Hz,1H),11.82(s,1H)。MS(ES)C24H30ClN3O2Si要求:455,实测:456(M+H)+。
步骤2:7-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-1,2,3,4-
四氢喹啉(G2)
在室温将在50%的TFA于DCM中的溶液(20mL)中的7-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-甲酸叔丁酯G1(1.0g,2.19mmol)搅拌2h。蒸发溶剂产生作为棕色固体的期望产物G2,其不经纯化用于下一步。MS(ES)C19H22ClN3Si要求:355,实测:356(M+H)+。
步骤3:1-(7-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二
氢喹啉-1(2H)-基)丙-2-烯-1-酮(G3)
在0℃向G2(2.19mmol,1.0当量)和DIPEA(2.5mL,14.5mmol,5.0当量)在无水DCM(40mL)中的溶液中缓慢地加入在无水DCM(5mL)中的丙烯酰氯(235mg,2.6mmol,1.0当量)。将混合物搅拌10min。将溶液用EtOAc稀释并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至1:1)纯化以产生作为白色固体的期望产物G3(581mg,1.42mmol,65%)。MS(ES)C22H24ClN3OSi要求:409,实测:410(M+H)+。
步骤4:1-(7-(4-氯-2-碘-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-
基)丙-2-烯-1-酮(G4)
将1-(7-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮G3(371mg,0.91mmol,1.0当量)和N-碘琥珀酰亚胺(366mg,1.63mmol,1.8当量)溶解在无水二氯甲烷(300mL)中并在室温搅拌15h。将有机相用饱和Na2S2O3水溶液洗涤1次和用饱和NaHCO3水溶液洗涤3次。将有机相经Na2SO4干燥并在真空中除去溶剂,产生作为黄色固体的期望产物G4。将粗制物不经纯化用在下一步中。MS(ES)C19H15ClIN3O要求:462,实测:463(M+H)+。
步骤5:1-(7-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(G5)
将1-(7-(4-氯-2-碘-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮G4(50mg,0.10mmol,1.0当量)、4-(4-甲基哌嗪-1-基)苯基硼酸(31mg,0.14mmol,1.5当量)和K3PO4(38mg,0.18mmol,2.0当量)在二烷/H2O(3mL/0.6mL)中的混合物用N2气流脱气5min。加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷加成化合物(8mg,0.01mmol,0.1当量)并将反应混合物在微波炉中加热至130℃保持2h。将粗制的反应混合物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物G5(22mg,0.03mmol,30%)。1H NMR(400MHz,d6-DMSO,300K)δ1.92(q,J=6.5Hz,2H),2.52(m,2H),2.79(t,J=6.5Hz,2H),2.85(s,3H),2.96(t,J=12.2Hz,2H),3.12(m,2H),3.51(d,J=12.2Hz,2H),3.75(m,2H),5.22(dd,J=2.4Hz,J=10.2Hz,1H),6.03(dd,J=2.4Hz,J=16.7Hz,1H),6.25(dd,J=10.2Hz,J=16.7Hz,1H),6.88(s,1H),6.99(d,J=9.0Hz,2H),7.12(d,J=5.2Hz,1H),7.21(dd,J=1.6Hz,J=7.6Hz,1H),7.28(d,J=7.6Hz,1H),7.31(d,J=9.0Hz,2H),8.15(d,J=5.2Hz,1H),12.40(s,1H)。MS(ES)C30H30ClN5O要求:511,实测:512(M+H)+。
根据关于G5(实施例86)描述的规程制备下表中的实施例。
实施例96:
N-(5-(4-氯-2-(4-(哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯
基)丙烯酰胺2,2,2-三氟乙酸盐(H2)
步骤1:4-(4-(3-(3-丙烯酰氨基-4-甲基苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-2-
基)苯基)哌嗪-1-甲酸叔丁酯(H1)
将N-(5-(4-氯-2-碘-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺A4(100mg,0.22mmol,1.0当量)、4-(4-boc-哌嗪子基)苯基硼酸(105mg,0.34mmol,1.5当量)和K3PO4(97mg,0.44mmol,2.0当量)在二烷/H2O(3mL/0.6mL)中的混合物用N2气流脱气5min。加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷加成化合物(19mg,0.02mmol,0.1当量)并将反应混合物在微波炉中加热至130℃保持2h。将反应混合物用EtOAc稀释,用饱和NaHCO3水溶液洗涤3次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至0:100)纯化以产生作为米色固体的期望产物H1(41mg,0.07mmol,32%)。MS(ES)C32H34ClN5O3要求:571,实测:572(M+H)+。
步骤2:N-(5-(4-氯-2-(4-(哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-
甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(H2)
在室温将在30%的TFA于DCM中的溶液(5mL)中的4-(4-(3-(3-丙烯酰氨基-4-甲基苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-2-基)苯基)哌嗪-1-甲酸叔丁酯H1(41mg,0.07mmol)搅拌2h。蒸发溶剂以后,将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物H2(18mg,0.02mmol,37%)。1H NMR(400MHz,d4-MeOH,300K)δ2.11(s,3H),3.14(m,4H),3.22(m,4H),5.57(dd,J=1.3Hz,J=10.2Hz,1H),6.13(dd,J=1.3Hz,J=16.9Hz,1H),6.30(dd,J=10.2Hz,J=16.9Hz,1H),6.75(d,J=8.8Hz,2H),6.90(m,2H),7.03(d,J=7.8Hz,1H),7.23(m,3H),7.89(d,J=5.4Hz,1H)。MS(ES)C27H26ClN5O要求:471,实测:472(M+H)+。
实施例97:
N-(5-(5-氰基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-
2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(I5)
步骤1:3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-
5-甲腈(I1)
按照在制备实施例1步骤1中报告的一般规程,从6-氨基-5-溴烟腈(3.6g,18.2mmol,1.00当量)和三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷(4.5g,19.0mmol,1.05当量)制备I1(2.6g,7.43mmol,40%,黄色固体)。MS(ES)C18H18N4O2Si要求:350,实测:351(M+H)+。
步骤2:3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-
5-甲腈(I2)
将3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-5-甲腈I1(270mg,0.8mmol,1.0当量)和N-碘琥珀酰亚胺(208mg,0.96mmol,1.2当量)溶解在无水二氯甲烷(40mL)中并在室温搅拌15h。将有机相用饱和Na2S2O3水溶液洗涤1次和用饱和NaHCO3水溶液洗涤3次。将有机相经Na2SO4干燥并在真空中除去溶剂,产生作为棕色固体的期望产物I2(123mg,0.30mmol,38%)。将粗制物不经纯化用在下一步中。MS(ES)C15H9IN4O2要求:403,实测:404(M+H)+。
步骤3:3-(4-甲基-3-硝基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲腈(I3)
将3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-5-甲腈I2(1.41g,3.5mmol,1.0当量)、4-(4-甲基哌嗪-1-基)苯基硼酸(1.14mg,5.2mmol,1.5当量)和K3PO4(1.47g,7.0mmol,2.0当量)在二烷/H2O(40mL/4mL)中的混合物用N2气流脱气5min。加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷加成化合物(284mg,0.35mmol,0.1当量)并将反应混合物在微波炉中加热至130℃保持2h。将反应混合物用EtOAc稀释,用饱和NaHCO3水溶液洗涤3次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(DCM/含有0.1%NEt3的MeOH=100:0至1:1)纯化以产生作为黄色固体的期望产物I3(500mg,1.10mmol,32%)。MS(ES)C26H24N6O2要求:452,实测:453(M+H)+。
步骤4:3-(3-氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲腈(I4)
按照在制备实施例1步骤2中报告的一般规程,从I3制备I4(93mg,0.22mmol)。MS(ES)C18H18N4O2Si要求:350,实测:351(M+H)+。
步骤5:N-(5-(5-氰基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-
3-基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(I5)
在0℃向I4(30mg,0.071mmol,1.0当量)和DIPEA(92mg,0.71mmol,10.0当量)在无水DCM(2mL)中的溶液中缓慢地加入在无水DCM(1mL)中的丙烯酰氯(32mg,0.355mmol,5.0当量)。将混合物搅拌5min。将粗制的溶液通过反相RP-HPLC(柱:C18)直接纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物I6(3mg,0.004mmol,5%)。1H NMR(400MHz,d4-MeOH,300K)δ2.31(s,3H),2.95(s,3H),3.30-3.48(m,8H),5.79(dd,J=1.6Hz,J=10.2Hz,1H),6.36(dd,J=1.6Hz,J=17.0Hz,1H),6.52(dd,J=10.2Hz,J=17.0Hz,1H),7.02(d,J=9.0Hz,2H),7.09(d,J=8.1Hz,1H),7.27(d,J=7.8Hz,1H),7.50(m,3H),8.23(d,J=1.9Hz,1H),8.51(d,J=1.9Hz,1H)。MS(ES)C29H28N6O要求:476,实测:477(M+H)+。
实施例98:
1-(6-(4-氯-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2H-苯并[b][1,4]
嗪-4(3H)-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(J4)
在室温将在30%的TFA于DCM中的溶液(20mL)中的6-(4-氯-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)-2H-苯并[b][1,4]嗪-4(3H)-甲酸叔丁酯F1(3489mg,7.62mmol)搅拌2h。蒸发溶剂产生棕色固体,将其通过硅胶上的快速色谱法(DCM/MeOH=100:0至5:1)纯化以产生作为黄色固体的期望产物J1(2726mg,7.62mmol,100%)。MS(ES)C18H20ClN3OSi要求:357,实测:358(M+H)+。
按照在制备实施例1步骤3规程A中报告的一般规程,从J1制备J2(635mg,1.54mmol,55%,白色固体)。MS(ES)C21H22ClN3O2Si要求:411,实测:412(M+H)+。
按照在制备实施例1步骤4中报告的一般规程,从J2制备J3(465mg,1.00mmol,100%,黄色固体)。MS(ES)C18H13ClN3O2要求:465,实测:466(M+H)+。
步骤4:1-(6-(4-氯-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡
啶-3-基)-2H-苯并[b][1,4]
嗪-4(3H)-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(J4)
按照在制备实施例1步骤5中报告的一般规程,从J3和2-(4-甲基哌嗪子基)吡啶-4-硼酸频哪醇酯制备J4(7.4mg,0.01mmol,9%,黄色固体)。1H NMR(400MHz,d6-DMSO,300K)δ2.86(s,3H),3.06(m,4H),3.50(d,J=10.3Hz,2H),4.27-4.40(m,6H),5.52(d,J=10.6Hz,1H),6.15(dd,J=1.9Hz,J=16.9Hz,1H),6.59(m,1H),6.66(d,J=5.3Hz,1H),7.00(d,J=8.3Hz,1H),7.03(s,1H),7.12(d,J=7.6Hz,1H),7.20(d,J=5.1Hz,1H),8.10(d,J=5.3Hz,1H),8.26(d,J=5.1Hz,1H),9.73(s,1H),12.66(s,1H)。MS(ES)C28H27ClN6O2要求:514,实测:515(M+H)+。
根据关于J4(实施例98)描述的规程制备下表中的实施例。
实施例104:
1-(6-(4-乙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)
吲哚啉-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(K5)
步骤1:6-(4-乙氧基-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚
啉-1-甲酸叔丁酯(K1)
按照在制备实施例1步骤1中报告的一般规程,从4-乙氧基-3-碘吡啶-2-胺和6-((三甲基甲硅烷基)乙炔基)吲哚啉-1-甲酸叔丁酯制备K1(3.74g,8.29mmol,73%,黄色固体)。MS(ES)C25H33N3O3Si要求:451,实测:452(M+H)+。
步骤2:4-乙氧基-3-(吲哚啉-6-基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡
啶(K2)
在室温将在30%的TFA于DCM中的溶液(60mL)中的6-(4-乙氧基-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-甲酸叔丁酯K1(1.5g,3.3mmol)搅拌2h。蒸发溶剂产生棕色固体。向粗制物中加入饱和NaHCO3水溶液并将混合物用DCM萃取3次。将有机相经MgSO4干燥并在真空中除去溶剂。将具有4-乙氧基-3-(吲哚啉-6-基)-1H-吡咯并[2,3-b]吡啶杂质的期望产物K2不经进一步纯化地用在下一步中。MS(ES)C20H25N3OSi要求:351,实测:352(M+H)+。
步骤3:1-(6-(4-乙氧基-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-3-基)吲
哚啉-1-基)丙-2-烯-1-酮(K3)
按照在制备实施例1步骤3规程A中报告的一般规程,从K2制备K3(371mg,0.91mmol,32%,白色固体)。MS(ES)C23H2N3O2Si要求:405实测:406(M+H)+。
步骤4:1-(6-(4-乙氧基-2-碘-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-
烯-1-酮(K4)
按照在制备实施例1步骤4中报告的一般规程,从K3制备K4(380mg,0.83mmol,黄色固体)。MS(ES)C20H18IN3O2要求:459,实测:460(M+H)+。
步骤5:1-(6-(4-乙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡
啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(K5)
按照在制备实施例1步骤5中报告的一般规程,从K4和4-(4-甲基哌嗪-1-基)苯基硼酸制备K5(14mg,0.019mmol,17%,黄色固体)。1H NMR(400MHz,d6-DMSO,300K)δ1.09(t,J=6.9Hz,3H),2.85(s,3H),2.97(t,J=12.6Hz,2H),3.12(m,2H),3.21(t,J=8.5Hz,2H),3.51(d,J=11.9Hz,2H),3.91(d,J=13.3Hz,2H),4.11(quart.,J=6.9Hz,2H),4.26(t,J=8.5Hz,2H),5.80(d,J=10.3Hz,1H),6.25(d,J=16.5Hz,1H),6.76(m,2H),6.91(d,J=7.6Hz,1H),6.96(d,J=8.5Hz,2H),7.17(d,J=7.6Hz,1H),7.34(d,J=8.5Hz,2H),8.19(d,J=6.0Hz,1H),8.25(s,1H),9.79(s,1H),12.39(s,1H)。MS(ES)C31H33N5O2要求:507,实测:508(M+H)+。
根据关于K5(实施例104)描述的规程制备下表中的实施例。
在步骤1中使用4-甲氧基-3-碘吡啶-2-胺作为起始原料,根据关于K5(实施例104)描述的规程制备下表中的实施例。
实施例115:
1-(6-(4-异丙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)吲哚啉-1-基)丙-2-烯-1-酮2,2,2-三氟乙酸盐(L1)
在步骤1中使用3-碘-4-异丙氧基吡啶-2-胺作为起始原料,根据关于K5(实施例104)描述的规程制备L1(15mg,0.2mmol,黄色固体)。1H NMR(400MHz,d6-DMSO,300K)δ1.13(d,J=6.0Hz,6H),2.85(s,3H),3.00(m,2H),3.12(m,2H),3.22(t,J=8.3Hz,2H),3.50(m,2H),3.92(m,2H),4.27(t,J=8.3Hz,2H),4.85(quint.,J=6.0Hz,1H),5.80(d,J=10.3Hz,1H),6.25(d,J=16.6Hz,1H),6.77(d,J=10.3Hz,J=16.6Hz,1H),6.90(d,J=7.6Hz,1H),6.94(d,J=6.5Hz,1H),6.98(d,J=8.5Hz,2H),7.18(d,J=7.6Hz,1H),7.35(d,J=8.5Hz,2H),8.27(m,2H),10.02(s,1H),12.81(s,1H)。MS(ES)C32H35N5O2要求:521,实测:522(M+H)+。
实施例116:
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸2,2,2-三氟乙酸盐(M3)
步骤1:3-(4-甲基-3-硝基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸盐酸(M1)
将3-(4-甲基-3-硝基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲腈I3(3.0g,6.6mmol)在浓HCl水溶液(50mL)中的混合物在100℃加热3h。在真空中除去溶剂,产生作为棕色固体的期望产物M1(3.1g,6.6mmol)。MS(ES)C26H25N5O4要求:471,实测:472(M+H)+。
步骤2:3-(3-氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸(M2)
将3-(4-甲基-3-硝基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸M1(3.0g,6.6mmol,1.0当量)和铁(1.8g,31.8mmol,5当量)在EtOH(100mL)和饱和NH4Cl水溶液(20mL)中的混合物在80℃加热15h。在真空中除去溶剂,并将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物M2(1.7g,4.0mmol,60%)。MS(ES)C26H27N5O2要求:441,实测:442(M+H)+。
步骤3:3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯
并[2,3-b]吡啶-5-甲酸2,2,2-三氟乙酸盐(M3)
在0℃向3-(3-氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸M2(580mg,1.31mmol,1.0当量)和DIPEA(2.3mL,13.1mmol,10当量)在无水THF(10ml)中的溶液中缓慢地加入在无水THF(1mL)中的丙烯酰氯(0.11mL,1.31mmol,1.0当量)。10min以后加入一滴水并在真空中除去溶剂。将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物M3(170mg,0.34mmol,26%)。1H NMR(400MHz,d6-DMSO,300K)δ2.27(s,3H),2.85(s,3H),3.01(t,J=12.5Hz,2H),3.13(m,2H),3.51(d,J=12.0Hz,2H),3.93(d,J=13.3Hz,2H),5.74(dd,J=10.1Hz,J=2.0Hz,1H),6.22(dd,J=17.1Hz,J=2.0Hz,1H),6.56(dd,J=17.1Hz,J=10.1Hz,1H),7.03(m,3H),7.27(d,J=7.9Hz,1H),7.47(d,J=6.4Hz,2H),7.60(s,1H),8.26(d,J=2.0Hz,1H),8.80(d,J=2.0Hz,1H),9.55(s,1H),9.72(br s,1H),12.41(s,1H),12.86(br s,1H)。MS(ES)C29H29N5O3要求:495,实测:496(M+H)+。
实施例117:
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(N3)
步骤1:3-(4-甲基-3-硝基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸异丙酯(N1)
将3-(4-甲基-3-硝基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲腈I3(100mg,0.2mmol)和浓H2SO4(1mL)在异丙醇(2mL)中的混合物在80℃加热48h。冷却至室温后,加入EtOAc和饱和NaHCO3水溶液。将水相用EtOAc(3x)萃取并将合并的有机相经MgSO4干燥。蒸发溶剂,产生作为黄色固体的N1的粗产物(28mg,0.05mmol,27%)。将粗制物不经进一步纯化地用于下一步。MS(ES)C29H31N5O4要求:513,实测:514(M+H)+。
步骤2:3-(3-氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸异丙酯(N2)
将在EtOH(5mL)和饱和NH4Cl水溶液(1mL)中的3-(4-甲基-3-硝基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯N1(28mg,0.05mmol,1.0当量)和铁(15mg,0.3mmol,5当量)在80℃加热3h。加入饱和NaHCO3水溶液并将水相用DCM(3x)萃取。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(DCM/含有0.1%NEt3的MeOH=100:0至1:1)纯化以产生作为棕色固体的期望产物N2(25mg,0.05mmol,94%)。MS(ES)C29H33N5O2要求:483,实测:484(M+H)+。
步骤3:3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯
并[2,3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(N3)
按照在制备实施例98步骤3中报告的一般规程,从N2制备N3(2mg,0.003mmol,4%,黄色固体)。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物N3。1H NMR(400MHz,d6-DMSO,300K)δ1.31(d,J=6.2Hz,6H),2.26(s,3H),2.85(s,3H),2.98(t,J=13.0Hz,2H),3.10(m,2H),3.50(d,J=12.0Hz,2H),3.92(d,J=13.0Hz,2H),5.14(quint.,J=6.2Hz,1H),5.72(dd,J=10.2Hz,J=2.0Hz,1H),6.21(dd,J=17.1Hz,J=2.0Hz,1H),6.55(dd,J=10.2Hz,J=17.1Hz,1H),6.99(d,J=8.6Hz,2H),7.25(d,J=7.9Hz,1H),7.45(d,J=8.6Hz,2H),7.64(s,1H),8.31(d,J=2.0Hz,1H),8.79(d,J=2.0Hz,1H),9.50(s,1H),9.58(br.s,1H),12.43(s,1H)。MS(ES)C32H35N5O3要求:537实测:538(M+H)+。
实施例118:
3-(3-丙烯酰氨基-4-甲基苯基)-N-苄基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡
咯并[2,3-b]吡啶-5-甲酰胺2,2,2-三氟乙酸盐(O1)
将3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸M3(30mg,0.06mmol,1.0当量)、DIPEA(0.1mL,0.60mmol,10当量)和HATU(46mg,0.12mmol,2.0当量)在无水DMF(1mL)中的溶液在0℃搅拌5min。然后加入苄胺(13mg,0.12mmol,2.0当量)并将混合物在0℃搅拌30min。加入饱和NaHCO3水溶液并将混合物用EtOAc萃取。将合并的有机相经MgSO4干燥,并在真空中除去溶剂。将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物O1(10mg,0.01mmol,21%)。1H NMR(400MHz,d4-MeOH,300K)δ2.30(s,3H),2.97(s,3H),3.07(t,J=12.4Hz,2H),3.26(m,2H),3.61(d,J=12.4Hz,2H),3.93(d,J=13.7Hz,2H),4.59(s,2H),5.77(dd,J=10.2Hz,J=1.7Hz,1H),6.32(dd,J=17.0Hz,J=1.7Hz,1H),6.50(dd,J=10.2Hz,J=17.0Hz,1H),7.01(d,J=8.9Hz,2H),7.12(d,J=8.1Hz,1H),7.20-7.37(m,6H),7.50(d,J=8.9Hz,2H),7.54(s,1H),8.48(d,J=2.1Hz,1H),8.75(d,J=2.1Hz,1H)。MS(ES)C36H36N6O2要求:584实测:585(M+H)+。
根据关于O1(实施例118)描述的规程制备下表中的实施例。
实施例134:
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸甲酯2,2,2-三氟乙酸盐(P1)
将3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸M3(40mg,0.08mmol,1.0当量)、DMAP(5mg,0.04mmol,0.5当量)、N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐(17mg,0.09mmol,1.1当量)和无水甲醇(7mg,0.2mmol,2.5当量)在DCM(2mL)中的溶液在室温搅拌15h。将粗制的溶液通过反相RP-HPLC(柱:C18)直接纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物P1(20mg,0.03mmol,34%)。1H NMR(400MHz,d6-DMSO,300K)δ2.26(s,3H),2.84(s,3H),2.98(t,J=12.0Hz,2H),3.11(m,2H),3.50(t,J=12.0Hz,2H),3.84(s,3H),3.92(d,J=13.3Hz,2H),5.72(dd,J=10.2Hz,J=2.0Hz,1H),6.21(dd,J=17.0Hz,J=2.0Hz,1H),6.54(dd,J=17.0Hz,J=10.2Hz,1H),6.99(d,J=9.0Hz,2H),7.02(m,1H),7.26(d,J=7.9Hz,1H),7.44(d,J=9.0Hz,2H),7.58(s,1H),8.26(d,J=2.1Hz,1H),8.80(d,J=2.1Hz,1H),9.52(s,1H),9.72(s,1H),12.45(s,1H)。MS(ES)C30H31N5O3要求:509实测:510(M+H)+。
根据关于P1(实施例134)描述的规程制备下表中的实施例。
实施例142:
(E)-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2-甲基苯基)丁-2-烯酰胺2,2,2-三氟乙酸盐(Q2)
步骤1:5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-
2-甲基苯胺(Q1)
按照在制备实施例97步骤2-4中报道的规程从4-氯-3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶A1制备Q1。MS(ES)C25H26ClN5要求:431实测:432(M+H)+。
步骤2:(E)-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡
啶-3-基)-2-甲基苯基)丁-2-烯酰胺2,2,2-三氟乙酸盐(Q2)
在0℃向Q1(20mg,0.05mmol,1.0当量)和DIPEA(60mg,0.46mmol,10.0当量)在无水THF(2mL)中的溶液中缓慢地加入在无水THF(0.5mL)中的巴豆酰氯(5mg,0.05mmol,1.1当量)。将混合物搅拌10min。将溶液用EtOAc稀释并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物Q2(13mg,0.02mmol,36%)。1H NMR(400MHz,d6-DMSO,300K)δ1.82(dd,J=7.0Hz,J=1.7Hz,3H),2.23(s,3H),2.82(s,3H),2.95(t,J=12.4Hz,2H),3.07(m,2H),3.43(m,2H),3.90(d,J=13.3Hz,2H),6.21(d,J=15.2Hz,1H),6.70(dq,J=7.0Hz,J=15.2Hz,1H),6.92(d,J=9.0Hz,2H),7.00(dd,J=7.5Hz,J=1.8Hz,1H),7.06(d,J=5.2Hz,1H),7.18(d,J=7.9Hz,1H),7.35(d,J=9.0Hz,2H),7.52(s,1H),8.12(d,J=5.2Hz,1H),9.21(s,1H),9.69(s,1H),12.30(s,1H)。MS(ES)C29H30ClN5O要求:500,实测:501(M+H)+。
实施例143:
(E)-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2-甲基苯基)-4-(二甲基氨基)丁-2-烯酰胺2,2,2-三氟乙酸盐(R1)
在0℃向反式-4-二甲基氨基巴豆酸盐酸盐(46mg,0.28mmol,3当量)和一滴无水DMF在无水DCM(1mL)中的溶液中缓慢地加入在无水DCM(0.2mL)中的草酰氯(20uL,0.23mmol,2.5当量)。1h以后,将该混合物加入Q1(40mg,0.09mmol,1.0当量)在无水DCM(1mL)和无水NMP(1mL)中的溶液中。将混合物搅拌10min。将溶液用DCM稀释并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物R1(26mg,0.03mmol,33%)。1H NMR(400MHz,d6-DMSO,300K)δ2.28(s,3H),2.80(s,6H),2.84(s,3H),2.97(t,J=12.6Hz,2H),3.09(m,2H),3.48(m,2H),3.93(m,2H),6.57(d,J=15.4Hz,1H),6.68(dt,J=7.0Hz,J=15.4Hz,1H),6.94(d,J=9.0Hz,2H),7.05(d,J=7.7Hz,1H),7.08(d,J=5.2Hz,1H),7.23(d,J=7.7Hz,1H),7.36(d,J=9.0Hz,2H),7.56(s,1H),8.14(d,J=5.2Hz,1H),9.65(s,1H),9.74(s,1H),12.34(s,1H)。MS(ES)C31H35ClN6O要求:543,实测:544(M+H)+。
实施例144:
N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-
甲基苯基)丙炔酰胺2,2,2-三氟乙酸盐(S1)
在0℃向Q1(70mg,0.16mmol,1.0当量)和DIPEA(0.28mL,1.62mmol,10.0当量)在无水THF(2mL)中的溶液中缓慢地加入在无水THF(0.5mL)中的3-(三甲基甲硅烷基)丙炔酰氯(29mg,0.18mmol,1.1当量)。将混合物搅拌10min。然后加入K2CO3(223mg,1.62mmol,10当量)并将溶液在0℃搅拌30min。将混合物直接通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物S1(30mg,0.04mmol,26%)。1H NMR(400MHz,d6-DMSO,300K)δ2.25(s,3H),2.85(s,3H),2.98(t,J=12.4Hz,2H),3.10(m,2H),3.48(d,J=12.0Hz,2H),3.92(d,J=13.3Hz,2H),4.32(s,1H),6.93(d,J=8.8Hz,2H),7.08(m,2H),7.23(d,J=7.8Hz,1H),7.31(s,1H),7.35(d,J=8.8Hz,2H),8.14(d,J=5.2Hz,1H),9.78(s,1H),10.23(s,1H),12.35(s,1H)。MS(ES)C28H26ClN5O要求:483,实测:484(M+H)+。
实施例145:
N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-
甲基苯基)乙烯磺酰胺2,2,2-三氟乙酸盐(T1)
在-10℃向Q1(25mg,0.06mmol,1.0当量)和三乙胺(0.10mL,0.58mmol,10.0当量)在无水THF(2mL)中的溶液中缓慢地加入在无水THF(0.5mL)中的2-氯乙磺酰氯(10mg,0.06mmol,1.1当量)。在-10℃搅拌2h以后,将混合物直接通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物T1(18mg,0.02mmol,40%)。1H NMR(400MHz,d6-DMSO,300K)δ2.32(s,3H),2.82(s,3H),2.95(m,2H),3.08(m,2H),3.42(m,2H),3.90(m,2H),5.79(d,J=9.8Hz,1H),5.80(d,J=16.4Hz,1H),6.64(dd,J=9.8Hz,J=16.4Hz,1H),6.91(d,J=9.0Hz,2H),7.07(d,J=5.2Hz,1H),7.08(d,J=1.8Hz,1H),7.13(d,J=1.8Hz,1H),7.21(d,J=7.7Hz,1H),7.27(d,J=9.0Hz,2H),8.12(d,J=5.2Hz,1H),9.22(s,1H),9.85(s,1H),12.33(s,1H)。MS(ES)C27H28ClN5O2S要求:522,实测:523(M+H)+。
实施例146:
2-氯-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2-甲基苯基)乙酰胺2,2,2-三氟乙酸盐(U1)
在0℃向Q1(30mg,0.07mmol,1.0当量)和DIPEA(0.12mL,0.69mmol,10.0当量)在无水THF(2mL)中的溶液中缓慢地加入在无水THF(0.5mL)中的氯乙酰氯(39mg,0.35mmol,5.0当量)。将混合物搅拌10min。然后加入饱和NaHCO3水溶液并将水相用DCM萃取。将合并的有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物U1(13mg,0.02mmol,25%)。1H NMR(400MHz,d6-DMSO,300K)δ2.25(s,3H),2.81(s,3H),2.96(t,J=12.6Hz,2H),3.08(m,2H),3.46(d,J=12.0Hz,2H),3.90(d,J=13.2Hz,2H),4.26(s,2H),6.91(d,J=8.9Hz,2H),7.04(d,J=7.6Hz,1H),7.07(d,J=5.2Hz,1H),7.20(d,J=7.6Hz,1H),7.34(d,J=8.9Hz,2H),7.43(s,1H),8.12(d,J=5.2Hz,1H),9.62(s,1H),9.73(s,1H),12.32(s,1H)。MS(ES)C27H27Cl2N5O要求:507,实测:508(M+H)+。
实施例147:
N-(5-(4-乙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(V1)
按照在制备实施例72步骤1-5中报告的一般规程,从3-碘-4-乙氧基吡啶-2-胺、三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷和4-(1-甲基-4-哌啶基)苯基硼酸频哪醇酯制备V1。MS(ES)C31H34N4O2要求:494,实测:495(M+H)+。
实施例148:
(E)-3-(3-(4-(二甲基氨基)丁-2-烯酰氨基)-4-甲基苯基)-2-(4-(4-甲基哌嗪-
1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(W1)
在0℃向反式-4-二甲基氨基巴豆酸盐酸盐(30mg,0.18mmol,3.5当量)和一滴无水DMF在无水THF(1mL)中的溶液中缓慢地加入在无水THF(0.2mL)中的草酰氯(14uL,0.16mmol,3.0当量)。90min以后,将混合物加入N2(25mg,0.05mmol,1.0当量)在无水NMP(1mL)中的溶液。将混合物搅拌10min。将溶液用DCM稀释并用饱和NaHCO3水溶液洗涤2次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物W1(13mg,0.01mmol,28%)。1H NMR(400MHz,d6-DMSO,300K)δ1.34(d,J=6.3Hz,6H),2.29(s,3H),2.81(s,6H),2.86(s,3H),3.04(m,2H),3.13(m,2H),3.43(m,2H),3.90(m,2H),3.94(d,J=7.0Hz,2H),5.16(七重峰,J=6.3Hz,1H),6.62(d,J=15.4Hz,1H),6.73(dt,J=15.4Hz,J=7.0Hz,1H),7.02(m,3H),7.27(d,J=7.9Hz,1H),7.47(d,J=8.9Hz,2H),7.67(s,1H),8.33(d,J=2.0Hz,1H),8.82(d,J=2.0Hz,1H),9.75(s,1H),10.02(s,1H),12.47(s,1H)。MS(ES)C35H42N6O3要求:594,实测:595(M+H)+。
实施例149:
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AA1)
按照在制备实施例97和117中报道的规程制备AA1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AA1。1H-NMR(400MHz,d6-DMSO,300K)δ1.34(d,J=6.2Hz,6H),1.82(q,J=13.2Hz,2H),2.05(d,J=13.2Hz,2H),2.28(s,3H),2.82(m,4H),3.08(q,J=12.0Hz,2H),5.15(七重峰,J=6.2Hz,1H),5.75(dd,J=2.0Hz,J=10.2Hz,1H),6.21(dd,J=2.0Hz,J=17.0Hz,1H),6.58(dd,J=10.2Hz,J=17.0Hz,1H),7.00(d,J=7.8Hz,1H),7.27(m,3H),7.54(d,J=8.1Hz,2H),7.66(s,1H),8.40(d,J=1.9Hz,1H),8.85(d,J=1.9Hz,1H),9.41(br s,1H),9.53(s,1H),12.56(s,1H)。MS(ES)C33H36N4O3要求:536实测:537(M+H)+。
根据关于AA1(实施例149)描述的规程制备下表中的实施例。
实施例150:
N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2,
3-二甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(AB1)
按照在制备实施例1中报告的一般规程,从4-氯-3-碘吡啶-2-胺和((3,4-二甲基-5-硝基苯基)乙炔基)三甲基硅烷制备AB1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AB1。1H-NMR(400MHz,d6-DMSO,300K)δ2.14(s,3H),2.26(s,3H),2.84(s,3H),2.87(m,2H),3.01(m,2H),3.12(m,2H),3.91(m,2H),5.70(dd,J=2.0Hz,J=10.1,1H),6.18(dd,J=2.0Hz,J=17.2Hz,1H),6.52(dd,J=10.1Hz,J=17.2Hz,1H),6.93(d,J=8.7Hz,2H),7.0(s,1H),7.05(d,J=5.2Hz,1H),7.26(s,1H),7.41(d,J=8.7Hz,2H),8.12(d,J=5.2Hz,1H),9.54(s,1H),9.81(br s,1H),12.28(s,1H)。MS(ES)C29H30ClN5O要求:500实测:501(M+H)+。
根据关于AB1(实施例150)描述的规程制备下表中的实施例。
实施例153:
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯
基)-1H-吡咯并[2,3-b]吡啶-5-甲酸2,2,2-三氟乙酸盐(AC1)
按照在制备实施例97和116中报告的一般规程制备AC1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AC1。1H-NMR(400MHz,d6-DMSO,300K)δ2.27(s,3H),2.83(s,3H),2.84(s,3H),2.94(s,3H),3.23(m,2H),3.66(m,2H),5.74(dd,J=2.1Hz,J=10.2Hz,1H),6.22(d,J=2.1Hz,J=17.1Hz,1H),6.55(dd,J=10.2Hz,17.1Hz,1H),6.79(d,J=9.1Hz,2H),7.04(d,J=7.9Hz,1H),7.28(d,J=7.9Hz,1H),7.44(d,J=9.1Hz,2H),7.58(s,1H),8.23(d,J=2.0Hz,1H),8.79(d,J=2.0Hz,1H),9.34(br s,1H),9.56(s,1H),12.34(s,1H),12.81(br s,1H)。MS(ES)C29H31N5O3要求:497实测:498(M+H)+。
实施例154:
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯
基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AD1)
按照在制备实施例98步骤3中报告的一般规程,从AC1和异丙醇制备AD1(8mg,0.01mmol,26%)。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AD1。1HNMR(400MHz,d6-DMSO,300K)δ1.33(d,J=6.3Hz,6H),2.28(s,3H),2.80(s,6H),2.95(s,3H),3.19(m,2H),3.68(t,J=7.4Hz,2H),5.15(七重峰,J=6.3Hz,1H),5.75(dd,J=1.9Hz,J=10.0Hz,1H),6.23(dd,J=1.9Hz,J=17.0Hz,1H),6.57(dd,J=10.0Hz,J=17.0Hz,1H),6.79(d,J=8.8Hz,2H),7.03(d,J=7.8Hz,1H),7.27(d,J=7.8Hz,1H),7.44(d,J=8.8Hz,2H),7.63(s,1H),8.29(d,J=2.0Hz,1H),8.79(d,J=2.0Hz,1H),9.55(s,1H),9.75(br s,1H),12.39(s,1H)。(ES)C32H37N5O3要求:539,实测:540(M+H)+。
实施例155:
N-(5-(5-氯-4-甲基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(AE1)
按照在制备实施例1中报告的一般规程,从3-溴-5-氯-4-甲基吡啶-2-胺和三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷制备AE1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AE1。1H-NMR(400MHz,d6-DMSO,300K)δ2.07(s,3H),2.28(s,3H),2.82/2.83(s,3H),2.94(t,J=12.6Hz,2H),3.08(m,2H),3.45(m,2H),3.88(d,J 13.2Hz,2H),5.71(dd,J=2.0Hz,J=10.1Hz,1H),6.20(dd,J=2.0Hz,J=17.1Hz,1H),6.52(dd,J=10.1Hz,J=17.1Hz,1H),6.90(d,J=8.8Hz,2H),7.02(d,J=7.8Hz,1H),7.24(d,7.8Hz,1H),7.34(d,J=8.8Hz,2H),7.56(s,1H),8.14(s,1H),9.46(s,1H),9.54(br s,1H),12,09(s,1H)。MS(ES)C29H30ClN5O要求:500实测:501(M+H)+。
实施例156:
3-(3-丙烯酰氨基-4-甲基苯基)-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯
并[2,3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AF5)
步骤1:3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-
5-甲酸异丙酯(AF1)
在N2气氛下将在无水DMF(120mL)中的6-氨基-5-碘烟酸异丙酯(11.4g,37.2mmol,1.0当量)、三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷(8.7g,37.2mmol,1.0当量)、1,4-二氮杂双环[2.2.2]辛烷(7.1g,63.2mmol,1.7当量)和二氯双(三苯基膦)钯(II)(2.6g,3.7mmol,0.1当量)分入六个微波瓶中。将每个瓶在145℃加热5h。在真空中除去溶剂并将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至1:1)纯化以产生作为米色固体的期望产物AF1(7.1g,17.3mmol,46%)。1H-NMR(400MHz,d6-DMSO,300K)δ0.23(s,9H),1.33(d,J=6.2Hz,6H),2.60(s,3H),5.15(七重峰,J=6.2Hz,1H),7.63(d,J=7.8Hz,1H),7.71(dd,J=1.9Hz,J=7.8Hz,1H),7.97(d,J=1.9Hz,1H),8.25(d,J=1.9Hz,1H),8.88(d,J=1.9Hz,1H),12.17(s,1H)。MS(ES)C21H25N3O4Si要求:411,实测:412(M+H)+。
步骤2:3-(3-氨基-4-甲基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-
5-甲酸异丙酯(AF2)
将3-(4-甲基-3-硝基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯AF1(7.1g,17.3mmol,1.0当量)和铁(2g,36.4mmol,2.1当量)在EtOH(360mL)和饱和NH4Cl水溶液(36mL)中的溶液在80℃搅拌8h。将溶液穿过垫过滤。在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至0:100)纯化以产生作为米色固体的期望产物AF2(5.4g,14.2mmol,82%)。MS(ES)C21H27N3O2Si要求:381,实测:382(M+H)+。
步骤3:3-(3-丙烯酰氨基-4-甲基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]
吡啶-5-甲酸异丙酯(AF3)
在-78℃向AF2(5.4g,14.2mmol,1.0当量)和DIPEA(24.7mL,141.7mmol,10.0当量)在无水THF(200mL)中的溶液中加入在无水THF(20mL)中的丙烯酰氯(1.53g,17.0mmol,1.2当量)。将混合物在-40℃搅拌20min,并然后加入几滴水。在真空中除去溶剂。将粗产物通过硅胶上的快速色谱法(cHex/EtOAc=100:0至1:1)纯化以产生作为黄色固体的期望产物AF3(6.2g,14.2mmol,定量)。MS(ES)C24H29N3O3Si要求:435,实测:436(M+H)+。
步骤4:3-(3-丙烯酰氨基-4-甲基苯基)-2-碘-1H-吡咯并[2,3-b]吡啶-5-甲酸异
丙酯(AF4)
将3-(3-丙烯酰氨基-4-甲基苯基)-2-(三甲基甲硅烷基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯AF3(6.2g,14.2mmol,1.0当量)和N-碘琥珀酰亚胺(4.2g,18.5mmol,1.3当量)溶解在无水二氯甲烷(700mL)中并在室温搅拌15h。将有机相用饱和Na2S2O3水溶液洗涤1次和用饱和NaHCO3水溶液洗涤2次。将有机相经Na2SO4干燥并在真空中除去溶剂。将粗制物在室温在DCM(30mL)中搅拌1h,将沉淀物滤出并在真空中干燥,产生作为米色固体的期望产物AF4(3.9g,8.0mmol,56%)。将粗制物不经纯化用在下一步中。1H-NMR(400MHz,d6-DMSO,300K)δ1.33(d,J=6.2Hz,6H),2.31(s,3H),5.16(七重峰,J=6.2Hz,1H),5.77(dd,J=2.2Hz,J=10.1Hz,1H),6.27(dd,J=2.2Hz,17.0Hz,1H),6.60(dd,J=10.1Hz,J=17.0Hz,1H),7.32(J=1.8Hz,J=7.8Hz,1H),7.39(d,J=7.8Hz,1H),7.78(s,1H),8.43(d,J=2.0Hz,1H),8.79(d,J=2.0Hz,1H),9.57(s,1H),12.84(s,1H)。MS(ES)C21H20IN3O3要求:489,实测:490(M+H)+。
步骤5:3-(3-丙烯酰氨基-4-甲基苯基)-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-
1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AF5)
将3-(3-丙烯酰氨基-4-甲基苯基)-2-碘-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯AF4(30mg,0.06mmol,1.0当量)、2-(4-甲基哌嗪子基)吡啶-4-硼酸频哪醇酯(24mg,0.08mmol,1.3当量)和K3PO4(26mg,0.12mmol,2.0当量)在二烷/H2O(5mL,10/1)中的混合物用N2气流脱气5min。加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷加成化合物(5mg,0.006mmol,0.1当量)并将反应混合物在N2气氛下在微波炉中加热至130℃保持2h。将反应混合物用EtOAc稀释,用饱和NaHCO3水溶液洗涤3次。将有机相经MgSO4干燥并在真空中除去溶剂。将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物AF5(8mg,0.01mmol,17%)。1H-NMR(400MHz,d6-DMSO,300K)δ1.34(d,J=6.2Hz,6H),2.31(s,3H),2.85(s,3H),3.07(m,2H),3.13(m,2H),3.50(d,J=11.7Hz,2H),4.35(d,J=13.8Hz,2H),5.17(七重峰,J=6.2Hz,1H),5.76(dd,J=2.1Hz,J=10.2Hz,1H),6.23(dd,J=2.1Hz,J=17.1Hz,1H),6.56(dd,J=10.2Hz,J=17.1Hz,1H),6.78(dd,J=1.3Hz,J=5.3Hz,1H),7.10(dd,J=1.8Hz,J=7.8Hz,1H),7.16(s,1H),7.35(d,J=7.8Hz,1H),7.64(s,1H),8.10(d,J=5.3Hz,1H),8.38(d,J=2.0Hz,1H),8.91(d,J=2.0Hz,1H),9.58(s,1H),9.78(br s,1H),12.75(s,1H)。MS(ES)C31H34N6O3要求:538,实测:539(M+H)+。
根据关于AF5(实施例156)描述的规程制备下表中的实施例。
实施例165:
3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯
并[2,3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AG1)
按照在制备实施例156中报告的一般规程,从6-氨基-5-碘烟酸异丙酯和((3-氟-4-甲基-5-硝基苯基)乙炔基)三甲基硅烷制备AG1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AG1。1H-NMR(400MHz,d6-DMSO,300K)δ1.34(d,J=6.2Hz,6H),2.18(s,3H),2.85/2.87(s,3H),3.02(t,J=12.4Hz,2H),3.14(q,J=12.4Hz,2H),3.51(m,2H),3.96(d,J=13.3Hz,2H),5.17(七重峰,J=6.2Hz,1H),5.87(dd,J=2.0Hz,J=10.2Hz,1H),6.25(dd,J=2.0Hz,J=17.1Hz,1H),6.57(dd,J=10.2Hz,J=17.1Hz,1H),6.87(d,J=10.4Hz,1H),7.05(d,J=8.8Hz,2H),7.47(d,J=8.8Hz,2H),7.54(s,1H),8.38(d,J=2.0Hz,1H),8.83(d,J=2.0Hz,1H),9.64(br s,1H),9.72(s,1H),12.53(s,1H)。MS(ES)C32H34FN5O3要求:555实测:556(M+H)+。
根据关于AG1(实施例165)描述的规程制备下表中的实施例。
实施例188:
N-(2-甲基-5-(2-(4-(4-甲基哌嗪-1-基)苯基)-5-(三氟甲氧基)-1H-吡咯并[2,
3-b]吡啶-3-基)苯基)丙烯酰胺2,2,2-三氟乙酸盐(AH1)
按照在制备实施例1中报告的一般规程,从3-溴-5-(三氟甲氧基)吡啶-2-胺和三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷制备AH1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AH1。1H-NMR(400MHz,d6-DMSO,300K)δ2.26(s,3H),2.86/2.87(s,3H),3.00(t,J=12.8Hz,2H),3.13(m,2H),3.52(d,J=12.0Hz,2H),3.96(d,J=13.3Hz,2H),5.75(dd,J=2.0Hz,J=10.0Hz,1H),6.25(dd,J=2.0Hz,J=17.1Hz,1H),6.57(dd,J=10.0Hz,J=17.1Hz,1H),6.98(d,J=7.8Hz,1H),7.02(d,J=9.0Hz,2H),7.23(d,J=7.8Hz,1H),7.46(d,J=9.0Hz,2H),7.63(s,1H),7.78(d,J=1.9Hz,1H),8.29(d,J=1.9Hz,1H),9.51(s,1H),9.66(br s,1H),12.36(s,1H)。MS(ES)C29H28F3N5O2要求:535实测:536(M+H)+。
实施例189:
2-(3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并
[2,3-b]吡啶-5-基)乙酸2,2,2-三氟乙酸盐(AI2)
步骤1:2-(3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-
吡咯并[2,3-b]吡啶-5-基)乙酸叔丁酯2,2,2-三氟乙酸盐(AI1)
按照在制备实施例1中报告的一般规程,从2-(6-氨基-5-溴吡啶-3-基)乙酸叔丁酯和三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷制备AI1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AI1。MS(ES)C34H39N5O3要求:565实测:566(M+H)+。
步骤2:2-(3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-
吡咯并[2,3-b]吡啶-5-基)乙酸2,2,2-三氟乙酸盐(AI2)
将AI1(245mg,0.31mmol)和TFA(2.5mL)在DCM(7.5mL)中的溶液在室温搅拌3h。在真空中除去溶剂。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AI2(172mg,0.23mmol,74%)。1H-NMR(400MHz,d6-DMSO,300K)δ2.26(s,3H),2.86/2.87(s,3H),2.98(t,J=12.1Hz,2H),3.13(m,2H),3.52(m,2H),3.65(s,2H),3.92(d,J=13.3Hz,2H),5.73(dd,J=2.0Hz,J=10.2Hz,1H),6.22(dd,J=2.0Hz,J=17.1Hz,1H),6.55(dd,J=10.2Hz,J=17.1Hz,1H),6.99(m,3H),7.24(d,J=7.9Hz,1H),7.45(d,J=8.9Hz,2H),7.56(s,1H),7.67(d,J=2.1Hz,1H),8.11(d,J=2.1Hz,1H),9.50(s,1H),9.60(br s,1H),11.95(s,1H),12.30(br s,1H)。MS(ES)C30H31N5O3要求:509实测:510(M+H)+。
实施例190:
2-(3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并
[2,3-b]吡啶-5-基)乙酸异丙酯2,2,2-三氟乙酸盐(AJ1)
按照在制备实施例134中报告的一般规程,从AI2和异丙醇制备AD1(2mg,0.003mmol,26%)。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AD1。1HNMR(400MHz,d4-MeOD,300K)δ1.22(d,J=6.3Hz,6H),2.30(s,3H),2.98(s,3H),3.07(m,2H),3.27(m,2H),3.60(m,2H),3.73(s,2H),3.93(m,2H),4.98(七重峰,J=6.3Hz,1H),5.79(dd,J=1.7Hz,10.0Hz,1H),6.35(dd,J=1.7Hz,J=17.0Hz,1H),6.51(dd,J=10.0Hz,J=17.0Hz,1H),7.01(d,J=9.0Hz,2H),7.09(d,J=7.9Hz,1H),7.23(d,J=7.9Hz,1H),7.50(m,3H),7.91(d,J=1.9Hz,1H),8.13(d,J=1.9Hz,1H)。MS(ES)C33H37N5O3要求:551实测:552(M+H)+。
根据关于AJ1(实施例190)描述的规程制备下表中的实施例。
实施例191:
N-(5-(5-乙基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-
2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(AK1)
按照在制备实施例1中报告的一般规程,从3-溴-5-乙基吡啶-2-胺和三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷制备AK1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AK1。1H-NMR(400MHz,d6-DMSO,300K)δ1.23(t,J=7.6Hz,3H),2.27(s,3H),2.69(q,J=7.6Hz,2H),2.86/2.87(s,3H),3.00(t,J=12.7Hz,2H),3.14(m,2H),3.51(m,2H),3.93(d,J=13.5Hz,2H),5.75(dd,J=2.0Hz,J=10.0Hz,1H),6.24(dd,J=2.0Hz,J=17.0Hz,1H),6.57(dd,J=10.0Hz,J=17.0Hz,1H),7.00(m,3H),7.23(d,J=7.7Hz,1H),7.44(d,J=7.0Hz,2H),7.61(s,1H),7.68(d,J=2.0Hz,1H),8.13(d,J=2.0Hz,1H),9.51(s,1H),9.70(br s,1H),11.90(s,1H)。MS(ES)C30H33N5O要求:479实测:480(M+H)+。
实施例192:
3-(1-丙烯酰基吲哚啉-6-基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-
b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AL1)
按照在制备实施例104中报告的一般规程,从6-氨基-5-碘烟酸异丙酯和6-((三甲基甲硅烷基)乙炔基)吲哚啉-1-甲酸叔丁酯制备AL1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AL1。1H NMR(400MHz,d4-MeOD,300K)δ1.30(d,J=6.1Hz,6H),2.84(s,3H),2.98(t,J=12.6Hz,2H),3.10(m,2H),3.23(m,2H),3.48(d,J=12.0Hz,2H),3.92(d,J=13.4Hz,2H),4.27(m,2H),5.13(七重峰,J=6.1Hz,1H),5.79(d,J=10.2Hz,1H),6.24(d,J=16.6Hz,1H),6.74(dd,J=10.2Hz,J=16.6Hz,1H),6.98(m,3H),7.29(d,J=7.7Hz,1H),7.44(d,J=8.7Hz,2H),8.21(s,1H),8.25(s,1H),8.80(d,J=2.0Hz,1H),9.65(br s,1H),12.44(s,1H)。MS(ES)C33H35N5O3要求:549实测:550(M+H)+。
实施例193:
N-(5-(5-乙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(AM1)
按照在制备实施例1中报告的一般规程,从3-溴-5-乙氧基吡啶-2-胺和三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷制备AM1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AM1。1H NMR(400MHz,d4-MeOD,300K)δ1.32(t,J=7.0Hz,3H),2.24(s,3H),2.84(s,3H),2.97(t,J=12.6Hz,2H),3.12(m,2H),3.50(d,J=12.0Hz,2H),3.88(d,J=13.4Hz,2H),4.05(q,J=7.0Hz,2H),5.72(dd,J=2.0Hz,J=10.1Hz,1H),6.22(dd,J=2.0Hz,J=17.1Hz,1H),6.55(dd,J=10.1Hz,J=17.1Hz,1H),6.94(d,J=8.0Hz,1H),6.98(d,J=9.0Hz,2H),7.18(d,J=8.0Hz,1H),7.42(m,3H),7.62(s,1H),7.96(d,J=2.7Hz,1H),9.49(s,1H),9.73(br s,1H),11.79(s,1H)。MS(ES)C30H33N5O2要求:495实测:496(M+H)+。
实施例194:
N-(5-(5-(2-(二甲基氨基)-2-氧代乙基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡
咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(AN1)
按照在制备实施例118中报告的一般规程从AI2和二甲基胺制备AN1(2mg,0.003mmol,26%)。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AN1。1HNMR(400MHz,d4-MeOD,300K)δ2.26(s,3H),2.81(s,3H),2.86(s,3H),2.99(t,J=12.6Hz,2H),3.04(s,3H),3.13(m,2H),3.51(m,2H),3.76(s,2H),3.92(d,J=13.3Hz,2H),5.74(dd,J=2.0Hz,J=10.1Hz,1H),6.22(dd,J=2.0Hz,J=17.0Hz,1H),6.55(dd,J=10.1Hz,J=17.0Hz,1H),6.99(m,3H),7.23(d,J=7.8Hz,1H),7.43(d,J=8.9Hz,2H),7.57(s,1H),7.62(d,J=2.0Hz,1H),8.08(d,J=2.0Hz,1H),9.50(s,1H),9.65(br s,1H),11.93(s,1H)。MS(ES)C32H36N6O2要求:536实测:537(M+H)+。
根据关于AN1(实施例194)描述的规程制备下表中的实施例。
实施例198:
3-(3-丙烯酰氨基-4-甲基苯基)-4-甲基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡
咯并[2,3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AO1)
按照在制备实施例1中报告的一般规程,从6-氨基-5-碘-4-甲基烟酸异丙酯和三甲基((4-甲基-3-硝基苯基)乙炔基)硅烷制备AO1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AO1。1H NMR(400MHz,d6-DMSO,300K)δ1.32(d,J=6.2Hz,6H),2.27(s,3H),2.30(s,3H),2.84/2.85(s,3H),2.96(t,J=12.8Hz,2H),3.08(m,2H),3.49(m,2H),3.90(d,J=13.4Hz,2H),5.12(七重峰,J=6.2Hz,1H),5.73(dd,J=2.0Hz,J=10.1Hz,1H),6.20(dd,J=2.0Hz,J=17.0Hz,1H),6.55(dd,J=10.1Hz,J=17.0Hz,1H),6.93(d,J=9.0Hz,2H),7.05(d,J=7.9Hz,1H),7.26(d,J=7.9Hz,1H),7.36(d,J=9.0Hz,2H),7.58(s,1H),8.60(s,1H),9.49(s,1H),9.59(br s,1H),12.28(s,1H)。MS(ES)C33H37N5O3要求:551实测:552(M+H)+。
根据关于AO1(实施例198)描述的规程制备下表中的实施例。
实施例199:
N-(5-(5-(羟基甲基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-
3-基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(AP3)
步骤1:3-(3-氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸甲酯2,2,2-三氟乙酸盐(AP1)
向3-(3-氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸M2(800mg,1.8mmol,1.0当量)在无水甲醇(12mL)中的溶液中加入亚硫酰氯(0.4mL)。将混合物在70℃搅拌15h。除去溶剂,并将粗制物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色粉末的标题化合物AP1(306mg,0.45mmol,25%)。1H NMR(400MHz,d6-DMSO,300K)δ2.15(s,3H),2.84(s,3H),2.98(t,J=12.6Hz,2H),3.11(m,2H),3.49(d,J=11.8Hz,2H),3.84(s,3H),3.91(d,J=13.2Hz,2H),6.61(m,1H),6.86(s,1H),6.99(d,J=9.0Hz,2H),7.06(d,J=7.6Hz,1H),7.45(d,J=9.0Hz,2H),8.23(d,J=2.1Hz,1H),8.80(d,J=2.1Hz,1H),9.70(brs,1H),12.39(s,1H)。MS(ES)C27H29N5O2要求:455,实测:456(M+H)+。
步骤2:(3-(3-氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-基)甲醇(AP2)
在0℃向AP1(306mg,0.45mmol,1.0当量)在无水THF(24mL)中的溶液中加入LiAlH4-溶液(1M,1.34mL,1.34mmol,3.0当量)。将混合物在0℃搅拌2h和在室温搅拌0.5h。将混合物冷却至0℃并再次加入LiAlH4-溶液(1M,0.45mL,0.45mmol,1.0当量)。1h以后,小心地加入饱和NaHCO3水溶液,并然后加入EtOAc。将沉淀物滤出并在真空中干燥,产生作为米色粉末的标题化合物AP2(25mg,0.06mmol,13%)。MS(ES)C26H29N5O要求:427,实测:428(M+H)+。
步骤3:N-(5-(5-(羟基甲基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]
吡啶-3-基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(AP3)
在0℃向AP2(25mg,0.06mmol,1.0当量)、DIPEA(30uL,0.18mmol,3.0当量)和HATU(34mg,0.09mmol,1.5当量)在无水DMF(1.5mL)中的溶液中加入丙烯酸(4mg,0.06mmol,1.0当量)在无水DMF(0.5mL)中的溶液。将混合物在0℃搅拌1h。将混合物用EtOAc稀释,并然后用饱和NaHCO3水溶液和盐水洗涤。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AP3(3mg,0.004mmol,73%)。1H NMR(400MHz,d6-DMSO,300K)δ2.24(s,3H),2.84(s,3H),2.97(t,J=12.6Hz,2H),3.13(m,2H),3.48(m,2H),3.90(d,J=13.4Hz,2H),4.54(s,2H),5.72(dd,J=2.0Hz,J=10.1Hz,1H),6.20(dd,J=2.0Hz,J=17.1Hz,1H),6.53(dd,J=10.1Hz,J=17.1Hz,1H),6.97(m,3H),6.22(d,J=7.8Hz,1H),7.43(d,J=8.9Hz,2H),7.56(s,1H),7.73(d,J=2.0Hz,1H),8.17(d,J=2.0Hz,1H),9.50(s,1H),9.65(br s,1H),11.93(s,1H)。MS(ES)C29H31N5O2要求:481实测:482(M+H)+。
实施例200:
N-(5-(5-异丁酰氨基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-
3-基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(AQ5)
步骤1:(2-甲基-5-(2-(4-(4-甲基哌嗪-1-基)苯基)-5-硝基-1H-吡咯并[2,3-b]
吡啶-3-基)苯基)氨基甲酸叔丁酯(AQ1)
按照在制备实施例1中报告的一般规程,从3-碘-5-硝基吡啶-2-胺和(2-甲基-5-((三甲基甲硅烷基)乙炔基)苯基)氨基甲酸叔丁酯制备AQ1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为橙色固体的标题化合物AQ1。1H NMR(400MHz,d6-DMSO,300K)δ1.42(s,9H),2.24(s,3H),2.84(s,3H),3.00(m,2H),3.11(m,2H),3.48(m,2H),3.94(d,J=13.2Hz,2H),6.95(dd,J=1.8Hz,J=7.7Hz,1H),7.01(d,J=8.9Hz,2H),7.20(d,J=7.7Hz,1H),7.44(m,1H),7.46(d,J=8.9Hz,2H),8.47(d,J=2.4Hz,1H),8.61(s,1H),9.09(d,J=2.4Hz,1H),9.75(br s,1H),12.83(s,1H)。MS(ES)C30H34N6O4要求:542实测:543(M+H)+。
步骤2:(5-(5-氨基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-
基)-2-甲基苯基)氨基甲酸叔丁酯(AQ2)
将(2-甲基-5-(2-(4-(4-甲基哌嗪-1-基)苯基)-5-硝基-1H-吡咯并[2,3-b]吡啶-3-基)苯基)氨基甲酸叔丁酯AQ1(40mg,0.05mmol,1.0当量)和铁(15mg,0.26mmol,5.0当量)在EtOH(1mL)和饱和NH4Cl水溶液(0.1mL)中的溶液在80℃搅拌3h。将溶液穿过垫过滤。在真空中除去溶剂。将粗制物溶解在DCM中并用饱和NaHCO3水溶液洗涤2次和用盐水洗涤1次。将有机相经MgSO4干燥并在真空中除去溶剂,产生作为米色固体的期望产物AQ2(23mg,0.04mmol,85%)。MS(ES)C30H36N6O2要求:512,实测:513(M+H)+。
步骤3:(5-(5-异丁酰氨基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡
啶-3-基)-2-甲基苯基)氨基甲酸叔丁酯(AQ3)
在0℃向AQ2(20mg,0.04mmol,1.0当量)和DIPEA(17uL,0.10mmol,2.50当量)在无水DCM(1mL)中的溶液中加入在无水DCM(0.5mL)中的异丁酰氯(4mg,0.04mmol,1.0当量)。将混合物在0℃搅拌1h和在室温搅拌1h。将混合物用DCM稀释并然后用饱和NaHCO3水溶液和盐水洗涤。将有机相经MgSO4干燥并在真空中除去溶剂。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AQ3(20mg,0.02mmol,63%)。MS(ES)C34H42N6O3要求:582,实测:583(M+H)+。
步骤4:N-(3-(3-氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并
[2,3-b]吡啶-5-基)异丁酰胺(AQ4)
将AQ3(19mg,0.02mmol)和TFA(1mL)在DCM(4mL)中的溶液在室温搅拌0.5h。在真空中除去溶剂,产生作为黄色固体的标题化合物AQ4(23mg,0.03mmol,定量)。MS(ES)C29H34N6O要求:482,实测:483(M+H)+。
步骤5:N-(5-(5-异丁酰氨基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]
吡啶-3-基)-2-甲基苯基)丙烯酰胺2,2,2-三氟乙酸盐(AQ5)
在-78℃向AQ4(23mg,0.03mmol,1.0当量)和DIPEA(47.4uL,0.28mmol,10.0当量)在无水DCM(2mL)中的溶液中加入在无水DCM(0.5mL)中的丙烯酰氯(3mg,0.03mmol,1.0当量)。将混合物在-78℃搅拌15min,并然后在0℃搅拌15min。再次加入在无水DCM(0.5mL)中的丙烯酰氯(3mg,0.03mmol,1.0当量)。15min以后,加入几滴水,并将混合物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AQ5(4mg,0.005mmol,19%)。1H NMR(400MHz,d6-DMSO,300K)δ1.10(d,J=6.8Hz,6H),2.27(s,3H),2.58(七重峰,J=6.8Hz,1H),2.85/2.86(s,3H),2.98(t,J=13.0Hz,2H),3.13(m,2H),3.51(d,J=12.1Hz,2H),3.91(d,J=13.3Hz,2H),5.73(dd,J=2.0Hz,J=10.2Hz,1H),6.20(dd,J=2.0Hz,J=17.0Hz,1H),6.55(dd,J=10.2Hz,J=17.0Hz,1H),6.98(d,J=9.0Hz,2H),7.00(m,1H),7.26(d,J=8.8Hz,1H),7.43(d,J=9.0Hz,2H),7.53(s,1H),8.06(d,J=2.3Hz,1H),8.36(d,J=2.3Hz,1H),9.51(s,1H),9.67(br s,1H),9.82(s,1H),11.87(s,1H)。MS(ES)C33H36N6O2要求:536实测:537(M+H)+。
根据关于AQ5(实施例200)描述的规程制备下表中的实施例。
实施例202:
3-(5-丙烯酰氨基-2,4-二甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并
[2,3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AR1)
按照在制备实施例1中报告的一般规程,从6-氨基-5-碘烟酸异丙酯和((2,4-二甲基-5-硝基苯基)乙炔基)三甲基硅烷制备AR1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AR1。1H NMR(400MHz,d6-DMSO,300K)δ1.31(d,J=6.2Hz,3H),1.32(d,J=6.2Hz,3H),1.86(s,3H),2.29(s,3H),2.86/2.87(s,3H),2.99(t,J=12.8Hz,2H),3.10(m,2H),3.50(d,J=12.1Hz,2H),3.95(d,J=13.6Hz,2H),5.15(七重峰,J=6.2Hz,1H),5.73(dd,J=2.0Hz,J=10.0Hz,1H),6.20(dd,J=2.0Hz,J=17.0Hz,1H),6.54(dd,J=10.0Hz,J=17.0Hz,1H),7.00(d,J=8.6Hz,2H),7.22(s,1H),7.43(d,J=8.6Hz,2H),7.46(s,1H),7.96(d,J=2.1Hz,1H),8.81(d,J=2.1Hz,1H),9.51(s,1H),9.68(br s,1H),12.51(s,1H)。MS(ES)C33H37N5O3要求:551实测:552(M+H)+。
实施例203:
3-(3-(丙烯酰氨基甲基)苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-
b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AS1)
按照在制备实施例83中报告的一般规程,从6-氨基-5-碘烟酸异丙酯和3-((三甲基甲硅烷基)乙炔基)苄基氨基甲酸叔丁酯制备AS1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AS1。1H NMR(400MHz,d6-DMSO,300K)δ1.34(d,J=6.2Hz,6H),2.87/2.88(s,3H),3.00(t,J=12.6Hz,2H),3.13(m,2H),3.51(m,2H),3.94(d,J=13.5Hz,2H),4.39(d,J=5.8Hz,2H),5.16(七重峰,J=6.2Hz,1H),5.61(dd,J=2.2Hz,J=10.2Hz,1H),6.11(dd,J=2.2Hz,J=17.0Hz,1H),6.26(dd,J=10.2Hz,J=17.0Hz,1H),7.00(d,J=9.2Hz,2H),7.23(d,J=7.6Hz,1H),7.27(d,J=7.6Hz,1H),7.34(s,1H),7.42(m,3H),8.24(d,J=2.1Hz,1H),8.64(t,J=5.8Hz,1H),8.83(d,J=2.1Hz,1H),9.66(br s,1H),12.51(s,1H)。MS(ES)C32H35N5O3要求:537实测:538(M+H)+。
实施例206:
3-(3-丙烯酰氨基-4-乙基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AT1)
按照在制备实施例1中报告的一般规程,从6-氨基-5-碘烟酸异丙酯和((4-乙基-3-硝基苯基)乙炔基)三甲基硅烷制备AT1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AT1。1H NMR(400MHz,d6-DMSO,300K)δ1.18(t,J=7.5Hz,3H),1.34(d,J=6.3Hz,6H),2.67(q,J=7.5Hz,2H),2.87(s,3H),3.01(t,J=12.6Hz,2H),3.11(m,2H),3.54(m,2H),3.96(d,J=13.4Hz,2H),5.17(七重峰,J=6.3Hz,1H),5.76(d,J=10.2Hz,1H),6.24(d,J=17.1Hz,1H),6.58(dd,J=10.2Hz,J=17.1Hz,1H),7.02(d,J=8.5Hz,2H),7.08(d,J=7.8Hz,1H),7.29(d,J=7.8Hz,1H),7.46(d,J=8.5Hz,2H),7.61(s,1H),8.38(d,J=2.0Hz,1H),8.82(d,J=2.0Hz,1H),9.95(s,1H),9.69(br s,1H),12.49(s,1H)。MS(ES)C32H37N5O3要求:551实测:552(M+H)+。
实施例207:
3-(3-丙烯酰氨基-2-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,
3-b]吡啶-5-甲酸异丙酯2,2,2-三氟乙酸盐(AU1)
按照在制备实施例1中报告的一般规程,从6-氨基-5-碘烟酸异丙酯和三甲基((2-甲基-3-硝基苯基)乙炔基)硅烷制备AU1。将粗产物通过反相RP-HPLC(柱:C18)纯化,使用H2O(0.1%TFA)和ACN(0.1%TFA)作为洗脱液。将期望的级分冷冻干燥以产生作为黄色固体的标题化合物AU1。1H NMR(400MHz,d6-DMSO,300K)δ1.31(d,J=6.2Hz,6H),1.88(s,3H),2.85(s,3H),2.98(t,J=12.6Hz,2H),3.10(m,2H),3.50(m,2H),3.93(d,J=13.4Hz,2H),5.14(七重峰,J=6.2Hz,1H),5.75(dd,J=2.0Hz,J=10.1Hz,1H),6.26(dd,J=2.0Hz,J=17.0Hz,1H),6.55(dd,J=10.1Hz,J=17.0Hz,1H),6.98(d,J=9.0Hz,2H),7.10(d,J=7.8Hz,1H),7.30(t,J=7.8Hz,1H),7.39(d,J=9.0Hz,2H),7.61(d,J=7.8Hz,1H),7.88(d,J=2.0Hz,1H),8.81(d,J=2.0Hz,1H),9.58(s,1H),9.68(br s,1H),12.52(s,1H)。MS(ES)C32H35N5O3要求:537实测:538(M+H)+。
根据关于AU1(实施例207)描述的规程制备下表中的实施例。
生物学测定
在下述测定之一中测试了本文描述的示例性化合物的活性,并发现具有小于10uM、特别小于500nM的IC50值:
1.HER2 INS YVMA激酶活性的测量
该方案描述了如何进行Lance激酶活性测定以确定通式(I)的化合物对HER2 INSYVMA的IC50值。该酶测定背后的原理是基于Ulight-肽底物的磷酸化。使用特异性的EU-标记的抗-磷酸肽抗体检测它。Eu标记的抗-磷酸肽抗体与磷酸化的ULight标记的肽的结合产生FRET-信号。
抑制剂与激酶的结合阻止Ulight-底物的磷酸化,从而导致FRET的丢失。在表2中总结了LANCE测定的相关信息。
表2:用于Her2 INS YVMA的试剂、储备液浓度和最终测定浓度
将在表3中概括的通式(I)的化合物从10mM DMSO储备溶液分8步1:3连续稀释,总体积为20μl。
对于每个样品,将8μl激酶-底物混合物转移进合适的测定板(例如Corning#3673)。使用Biomek FX自动仪(BeckmanCoulter)经由针工具转移(pintool transfer)(10nl/孔)添加化合物。通过添加2μl ATP工作溶液开始反应,并使用variomag远程振荡器(teleshaker)(Thermo Fischer Scientific)进行混合。在室温温育1h以后,用10μl含有Eu-标记的磷酸特异性抗体和10mM EDTA的检测混合物停止反应。在室温下经过1h的第二个温育时段后,用Envision分光光度计(Perkin Elmer,Waltham,MA,USA)在340nm激发、665nm和615nm发射(分别对于ULight-底物和Eu-AB)测量FRET信号,具有50μs延迟和300μs积分时间。使用软件Quattro Workflow(Quattro GmbH,慕尼黑,德国)从S形剂量响应曲线确定IC50值。
2.细胞活性的测量
CellTiter-Glo发光细胞生存力测定(CellTiter-Glo Luminescent CellViability Assay,Promega)是确定培养物中的活细胞数目的同质方法。它是基于ATP的定量,指示代谢活性的细胞的存在。在第1天以确保测定线性和最佳信号强度的细胞数目接种细胞。在37℃和5%CO2的控湿箱中温育24h后,以不同浓度添加在DMSO中的化合物。将细胞在37℃和5%CO2下进一步温育72h。用化合物媒介物DMSO处理的细胞用作阳性对照,且用10μM星形孢菌素处理的细胞充当阴性对照。在第5天,根据试剂盒(Promega Inc.)的说明书制备CellTiter Glo试剂:将试剂与细胞培养基1:1混合。在其上,将混合物和测定平板在室温平衡20min。将等体积的试剂-培养基混合物添加到在每个孔中存在的培养基体积中。将板在定轨摇床上以约200rpm混合2分钟。然后将微量培养板在室温温育10分钟以稳定发光信号。温育后,使用200ms积分时间在Victor微量培养板读数器(Perkin Elmer)上记录发光。然后使用XLFIT Plugin(剂量响应Fit 205)用Excel分析数据以确定IC50。作为质量控制,从16个阳性和阴性对照值计算Z′-因子。仅将显示Z′-因子≥0.5的测定结果用于进一步分析。
表3显示了在生化Her2外显子20INSYVMA Lance测定和细胞Her2外显子20INSYVMABa/F3 CellTiter-Glo和EGFR外显子20INSNPH Ba/F3 CellTiter-Glo测定中的活性数据。将抑制指示为IC50[nM](“-”=未测量)。具有称为“A”的活性的化合物提供了IC50≤100nM;具有称为“B”的活性的化合物提供了100nM<IC50≤500nM;具有称为“C”的活性的化合物提供了500nM<IC50≤1000nM;具有称为“D”的活性的化合物提供了1000nM<IC50≤10000nM;和具有称为“E”的活性的化合物提供了IC50>10000nM。
表3:
表4显示了在生化EGFR T790ML858R Lance和EGFR wt Lance测定和细胞H1975CellTiter-Glo、H1781 CellTiter-Glo和A431 CellTiter-Glo测定中的活性数据。将抑制指示为IC50[nM](“-”=未测量)。具有称为“A”的活性的化合物提供了IC50≤100nM;具有称为“B”的活性的化合物提供了100nM<IC50≤500nM;具有称为“C”的活性的化合物提供了500nM<IC50≤1000nM;具有称为“D”的活性的化合物提供了1000nM<IC50≤10000nM;和具有称为“E”的活性的化合物提供了IC50>10000nM。
表4:
3.代谢稳定性
由药物代谢酶催化的酶反应有两大类,即所谓的I相(phase)和II相反应。I相反应中的基本过程主要是由细胞色素P450(CYP)家族的酶催化的氧化、还原和/或水解。探索参照物1的代谢稳定性,我们已经观察到在有和没有辅因子NADPH的小鼠肝微粒体存在下,丙烯酰胺部分的水解是主要的代谢物。图2显示了在50分钟后在小鼠肝微粒体存在下参照物1的丙烯酰胺部分的水解。
以下规程描述了通过测量随时间的化合物消耗,使用肝微粒体确定试验化合物的体外I相代谢稳定性的方法。将3μM浓度的试验化合物与来自小鼠物种的肝微粒体一起温育,并在没有NADPH的情况下进行实验。通过LC-MS/MS在37℃测量试验化合物随着长达50分钟的时间的消耗。在这些条件下测试了不同化合物的微粒体稳定性(参见表5)。通过邻近(next to)丙烯酰胺部分引入取代基如甲基(如在实施例1中),或通过将参照物1的仲丙烯酰胺修饰为叔丙烯酰胺(如在实施例55中),防止丙烯酰胺部分的水解。
表5:在小鼠肝微粒体中在没有辅因子NADPH存在下的稳定性
4.SAR
由式(Ia和Ib)表示的本发明化合物的结构-活性关系(SAR)显示出作为细胞有效的突变体选择性的ErbB抑制剂的共价抑制剂。例如通过引入丙烯酸部分而获得的共价结合模式对于改善的生物化学和细胞活性而言是至关重要的。具有用于共价结合的丙烯酰基部分的本发明实施例与具有丙酸部分的相应分子的直接对比表明共价结合剂具有改善的细胞活性。
表6显示了共价抑制剂与对应的可逆类似物的对比。在所有情况下,共价抑制剂显示出与可逆类似物相比改善的细胞活性。
表6:共价抑制剂与对应的可逆类似物的对比.
序列表
SEQ-ID No.1:EGFR p.D440_N771insSVD
SEQ-ID No.2:EGFR p.H773_V774insNPH
SEQ-ID No.3:EGFR p.V769_D770insASV
SEQ-ID No.4:EGFR p.p772_H773insPR
SEQ-ID No.5:HRT2 INS8 INSYVMA
6.SEQ-ID No.6:EGFR T790M
7.SEQ-ID No.7:EGFR T790ML858R
序列表
<110> Lead Discovery Center GmbH
<120> 可用于治疗癌症的作为ErbB调节剂的4-取代的吡咯并[2,3-b]吡啶
<130> LDC-P03722WO
<160> 7
<170> PatentIn 3.5版
<210> 1
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 在BaF3中的EGFR p.D770_N771insSVD突变
<400> 1
ttcaaaaaga tcaaagtgct gggctccggt gcgttcggca cggtgtataa gggactctgg 60
atcccagaag gtgagaaagt taaaattccc gtcgctatca aggaattaag agaagcaaca 120
tctccgaaag ccaacaagga aatcctcgat gaagcctacg tgatggccag cgtggactca 180
gtagacaacc cccacgtgtg ccgcctgctg ggcatctgcc tcacctccac cgtgcagctc 240
atcacgcagc tcatgccctt cggctgcctc ctggactatg tccgggaaca caaagacaat 300
attggctccc agtacctgct caactggtgt gtgcagatcg caaag 345
<210> 2
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 在BaF3中的EGFR p.H773_V774insNPH突变
<400> 2
ttcaaaaaga tcaaagtgct gggctccggt gcgttcggca cggtgtataa gggactctgg 60
atcccagaag gtgagaaagt taaaattccc gtcgctatca aggaattaag agaagcaaca 120
tctccgaaag ccaacaagga aatcctcgat gaagcctacg tgatggccag cgtggacaac 180
ccccacaatc cacatgtgtg ccgcctgctg ggcatctgcc tcacctccac cgtgcagctc 240
atcacgcagc tcatgccctt cggctgcctc ctggactatg tccgggaaca caaagacaat 300
attggctccc agtacctgct caactggtgt gtgcagatcg caaag 345
<210> 3
<211> 345
<212> DNA
<213> 人工序列
<220>
<223> 在BaF3中的EGFR p.V769_D770insASV突变
<400> 3
ttcaaaaaga tcaaagtgct gggctccggt gcgttcggca cggtgtataa gggactctgg 60
atcccagaag gtgagaaagt taaaattccc gtcgctatca aggaattaag agaagcaaca 120
tctccgaaag ccaacaagga aatcctcgat gaagcctacg tgatggccag cgtggcctca 180
gtcgacaacc cccacgtgtg ccgcctgctg ggcatctgcc tcacctccac cgtgcagctc 240
atcacgcagc tcatgccctt cggctgcctc ctggactatg tccgggaaca caaagacaat 300
attggctccc agtacctgct caactggtgt gtgcagatcg caaag 345
<210> 4
<211> 342
<212> DNA
<213> 人工序列
<220>
<223> 在BaF3中的EGFR p.P772_H773insPR突变
<400> 4
ttcaaaaaga tcaaagtgct gggctccggt gcgttcggca cggtgtataa gggactctgg 60
atcccagaag gtgagaaagt taaaattccc gtcgctatca aggaattaag agaagcaaca 120
tctccgaaag ccaacaagga aatcctcgat gaagcctacg tgatggccag cgtggacaac 180
cccccgcgtc acgtgtgccg cctgctgggc atctgcctca cctccaccgt gcagctcatc 240
acgcagctca tgcccttcgg ctgcctcctg gactatgtcc gggaacacaa agacaatatt 300
ggctcccagt acctgctcaa ctggtgtgtg cagatcgcaa ag 342
<210> 5
<211> 501
<212> DNA
<213> 人工序列
<220>
<223> 在BaF3中的HER2 INS8 INS YVMA突变
<400> 5
acacctagcg gagcgatgcc caaccaggcg cagatgcgga tcctgaaaga gacggagctg 60
aggaaggtga aggtgcttgg atctggcgct tttggcacag tctacaaggg catctggatc 120
cctgatgggg agaatgtgaa aattccagtg gccatcaaag tgttgaggga aaacacatcc 180
cccaaagcca acaaagaaat cttagacgaa gcatacgtga tggcttacgt gatggctggt 240
gtgggctccc catatgtctc ccgccttctg ggcatctgcc tgacatccac ggtgcagctg 300
gtgacacagc ttatgcccta tggctgcctc ttagaccatg tccgggaaaa ccgcggacgc 360
ctgggctccc aggacctgct gaactggtgt atgcagattg ccaaggggat gagctacctg 420
gaggatgtgc ggctcgtaca cagggacttg gccgctcgga acgtgctggt caagagtccc 480
aaccatgtca aaattacaga c 501
<210> 6
<211> 980
<212> DNA
<213> 人工序列
<220>
<223> 在BaF3中的EGFR T790M突变
<400> 6
ggtgttccgg accccacaca gattcctaca ggccctcatg atattttaaa acacagcatc 60
ctcaaccttg aggcggaggt cttcataaca aagatactat cagttcccaa actcagagat 120
caggtgactc cgactcctcc tttatccaat gtgctcctca tggccactgt tgcctgggcc 180
tctctgtcat ggggaatccc cagatgcacc caggaggggc cctctcccac tgcatctgtc 240
acttcacagc cctgcgtaaa cgtccctgtg ctaggtcttt tgcaggcaca gcttttcctc 300
catgagtacg tattttgaaa ctcaagatcg cattcatgcg tcttcacctg gaaggggtcc 360
atgtgcccct ccttctggcc accatgcgaa gccacactga cgtgcctctc cctccctcca 420
ggaagcctac gtgatggcca gcgtggacaa cccccacgtg tgccgcctgc tgggcatctg 480
cctcacctcc accgtgcagc tcatcatgca gctcatgccc ttcggctgcc tcctggacta 540
tgtccgggaa cacaaagaca atattggctc ccagtacctg ctcaactggt gtgtgcagat 600
cgcaaaggta atcagggaag ggagatacgg ggaggggaga taaggagcca ggatcctcac 660
atgcggtctg cgctcctggg atagcaagag tttgccatgg ggatatgtgt gtgcgtgcat 720
gcagcacaca cacattcctt tattttggat tcaatcaagt tgatcttctt gtgcacaaat 780
cagtgcctgt cccatctgca tgtggaaact ctcatcaatc agctaccttt gaagaatttt 840
ctctttattg agtgctcagt gtggtctgat gtctctgttc ttatttctct ggaattcttt 900
gtgaatactg tggtgatttg tagtggagaa ggaatattgc ttcccccatt caggacttga 960
taacaaggta agcaagccag 980
<210> 7
<211> 980
<212> DNA
<213> 人工序列
<220>
<223> 在BaF3中的EGFR T790ML858R突变
<400> 7
tccaaactgc acctacggat gcactgggcc aggtcttgaa ggctgtccaa cgaatgggcc 60
taagatcccg tccatcgcca ctgggatggt gggggccctc ctcttgctgc tggtggtggc 120
cctggggatc ggcctcttca tgcgaaggcg ccacatcgtt cggaagcgca cgctgcggag 180
gctgctgcag gagagggagc ttgtggagcc tcttacaccc agtggagaag ctcccaacca 240
agctctcttg aggatcttga aggaaactga attcaaaaag atcaaagtgc tgggctccgg 300
tgcgttcggc acggtgtata agggactctg gatcccagaa ggtgagaaag ttaaaattcc 360
cgtcgctatc aaggaattaa gagaagcaac atctccgaaa gccaacaagg aaatcctcga 420
tgaagcctac gtgatggcca gcgtggacaa cccccacgtg tgccgcctgc tgggcatctg 480
cctcacctcc accgtgcagc tcatcatgca gctcatgccc ttcggctgcc tcctggacta 540
tgtccgggaa cacaaagaca atattggctc ccagtacctg ctcaactggt gtgtgcagat 600
cgcaaagggc atgaactact tggaggaccg tcgcttggtg caccgcgacc tggcagccag 660
gaacgtactg gtgaaaacac cgcagcatgt caagatcaca gattttgggc gggccaaact 720
gctgggtgcg gaagagaaag aataccatgc agaaggaggc aaagtgccta tcaagtggat 780
ggcattggaa tcaattttac acagaatcta tacccaccag agtgatgtct ggagctacgg 840
ggtgaccgtt tgggagttga tgacctttgg atccaagcca tatgacggaa tccctgccag 900
cgagatctcc tccatcctgg agaaaggaga acgcctccct cagccaccca tatgtaccat 960
cgatgtctac atgatcatgg 980
Claims (15)
1.式(I)的化合物或其对映异构体、对映异构体的混合物、非对映异构体、非对映异构体的混合物、互变异构体、水合物、溶剂化物或药学上可接受的盐
其中
A代表
B代表
R1代表-H、-R*、-CH2-R*、-CHRa-R*、-CRaRb-R*、-CH2CH2-R*、-CRaRb-CRcRd-R*、-CH=CH-R*、-CRa=CRb-R*、-CH2CH2CH2-R*或-CRaRb-CRcRd-CReRf-R*;
Ra-Rf彼此独立地代表-H、-F、-Cl、-CH3、-OCH3、-CH2CH3、-CH2CH2CH3、-CH(CH3)2、-CH2CH(CH3)2或-环-C3H5;
R*代表-H、-F、-Cl、-Br、-I、-OH、-CN、-NH2、-NHCH3、-NHC2H5、-NHC3H7、-NHCH(CH3)2、-NHC(CH3)3、-N(CH3)2、-N(C2H5)2、-N(C3H7)2、-N[CH(CH3)2]2、-N[C(CH3)3]2、-NO2、-OCH3、-OC2H5、OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-O-环-C3H5、-OCH2-环-C3H5、-O-C2H4-环-C3H5、-CHO、-COCH3、-COC2H5、-COC3H7、-COCH(CH3)2、-COC(CH3)3、-OOC-CH3、-OOC-C2H5、-OOC-C3H7、-OOC-CH(CH3)2、-OOC-环-C3H5、-OOC-环-C3H5、-OCF3、-OC2F5、-NHSO2CH3、-NHSO2C2H5、-NHSO2C3H7、-NHSO2CH(CH3)2、-NHSO2-环-C3H5、-SOCH3、-SO2CH3、-SO2CF3、-SO2C2H5、-SO2CH2CF3、-SO2C3H7、-SO2CH(CH3)2、-SO2-环-C3H5、-SO(NH)CH3、-SO(NH)C2H5、-SO(NH)C3H7、-SO(NH)CH(CH3)2、-SO(NH)-环-C3H5、-SO(NCH3)CH3、-SO(NCH3)C2H5、-SO(NCH3)C3H7、-SO(NCH3)CH(CH3)2、-SO(NCH3)-环-C3H5、
R2代表-H、-F、-Cl、-Br、-I、-OH、-CN、-CH3、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-O-环-C3H5、-OCH2-环-C3H5或-O-C2H4-环-C3H5;
R3代表-H、-CH3、-C2H4OH、-OC2H4OH、-NR27R28、-CH2NR27R28、-CH2CH2NR27R28、-CH2CH2CH2NR27R28、-NHCOR27、-NHSO2R27、-OCH2NR27R28、-OCH2CH2NR27R28、-OCH2CH2CH2NR27R28、-NR29CH2NR27R28、-NR29CH2CH2NR27R28、-NR29CH2CH2CH2NR27R28、-CONR27R28、-CONHCH2NR27R28、-CONHCH2CH2NR27R28、-CONHCH2CH2CH2NR27R28、
L是键、-CH2-、-CH(CH3)-、-CH2CH2-、-CH2CH2CH2-、-CF2-、-CF2CH2-、-OCH2-、-OCH2CH2-、-OCH2CH2CH2-、-NHCH2-、-NHCH2CH2-、-NHCH2CH2CH2-、-N(CH3)CH2-、-N(CH3)CH2CH2-、-N(CH3)CH2CH2CH2-、-NHCO-、-NHCOCH2-、-NHCOCH2CH2-、-CO-、-CH2CO-、-CH2CH2CO-、-COCH2-、-COCH2CH2-、-COCH2CO-、-COCH2CH2CO-、-CONH-、-CONHCH2-、-CONHCH2CH2-、-CONHCH2CH2CH2-、-OCO-、-SO2-、-CH2OCO-或-CH2CH2OCO-;
R4代表-H、-CH3或-C2H5;
R5代表
R8-R11彼此独立地代表-H、-F、-Cl、-CN、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-OCH2CH(CH3)2、-OC2H4OCH3、-CH2OCH3、-CH3、-CF3、-C2H5或-C3H7,
或者R8和R9或R9和R10一起形成-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2OCH2-、-CH2OCH2CH2-、-OCH2O-或-OCH2CH2O-;
R12-R16彼此独立地代表-H、-F、-Cl、-CN、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-OCH2CH(CH3)2、-OC2H4OCH3、-CH2OCH3、-CH3、-CF3、-C2H5或-C3H7;
R17-R21彼此独立地代表-H、-F、-Cl、-CN、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-OC(CH3)3、-OC4H9、-OCH2CH(CH3)2、-OC2H4OCH3、-CH2OCH3、-CH3、-CF3、-C2H5或-C3H7;
R22代表-H、-CH3、-CF3、-C2H5、-C3H7、-COCH3、-COC2H5、-SO2CH3或-SO2C2H5;
R23代表-H、-CH3、-CF3、-C2H5、-C3H7、-CH2CH2OCH3或-C4H9;
R24和R25彼此独立地代表-H、-CH3、-CF3、-C2H5、-C3H7、-CH2CH2OCH3、-CH(CH3)2、-C4H9、-环-C3H5、-环-C4H7、-环-C5H9、-环-C6H11、
或者R24和R25一起形成-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2OCH2-或-CH2OCH2CH2-;
L1代表键、-CH2-、-CH2CH2-或-CH2CH2CH2-;
R26代表-H、-CH3、-C2H5、-C3H7、-CH2CH2OCH3、-CH(CH3)2、-C4H9、-环-C3H5、-环-C4H7、-环-C5H9、-环-C6H11、-C(CH3)3、-Ph或-CH2Ph;
R27-R31彼此独立地代表-H、-F、-Cl、-OH、-CN、-NH2、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-CH3、-CF3、-C2H5、-C3H7、-CH2CH2OCH3、-CH(CH3)2、-C4H9、-环-C3H5、-环-C4H7、-环-C5H9或-环-C6H11;
R32、R37、R38和R43彼此独立地代表-H、-CH3、-CF3、-C2H5、-C3H7、-CH(CH3)2、-Ph、-CH2Ph、-COCH3、-COCF3、-COC2H5、-COCH(CH3)2、-COC(CH3)3、-COPh、-CO2CH3、-CO2C2H5、-CO2CH(CH3)2、-CO2C(CH3)3、-CO2Ph、-CO2CH2Ph、-SO2CH3、-SO2C2H5、-SO2CF3或-SO2Ph;
R33、R34、R35和R36彼此独立地代表-H、-CH3、-CF3、-C2H5、-C3H7、-CH(CH3)2、-CN、-NO2、-COCH3、-COC2H5、-COC3H7、-COCH(CH3)2、-COC(CH3)3、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COOCH(CH3)2或-COOC(CH3)3;
R39代表-F、-Br、-Cl或-I;
R40、R41和R42彼此独立地代表-H、-F、-Cl、-OH、-CN、-NH2、-CH3、-CF3、-C2H5、-C3H7、-CH(CH3)2、-OCH3、-OC2H5、-OC3H7、-OCH(CH3)2、-COCH3、-COCF3、-COC2H5、-COCH(CH3)2、-NHCH3、-NHC2H5、-N(CH3)2、-N(C2H5)2、-NHCOCH3、-NHCOCF3、-NHCOC2H5、-NHCOCH(CH3)2、-CO2H、-CO2CH3、-CO2C2H5、-CO2CH(CH3)2、-CO2Ph、-CO2CH2Ph、-CONH2、-CONHCH3、-CONHC2H5、-CONHCH(CH3)2、-CON(CH3)2、-SO2CH3、-SO2C2H5、-SO2CF3、-SO2Ph、-SO2NH2、-SO2NHCH3、
5.根据权利要求1-4中的任一项所述的化合物,其中
R1代表-H、-CN、-C2H5、-OC2H5、-OCF3、-CH2OH、-COOH、-COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOCH2CH2OCH3、-COO-环-C3H5、-COO-环-C4H7、-COO-环-C5H9、-COO-环-C6H11、-CONHCH(CH3)2、-CONH-环-C6H11、-CH2COOH、-CH2COOCH3、-CH2COOCH(CH3)2、-CH2CONH(CH3)、-CH2CON(CH3)2、-NHCOCH3、-NHCOCH(CH3)2,
R2代表-H、-Cl、-OCH3、-OC2H5或-OCH(CH3)2;
B代表
R3代表-H、-CH2N(CH3)2、-CH2CH2N(CH3)2、-OCH2CH2N(CH3)2、-OCH2CH2CH2N(CH3)2、-CH2N(CH3)2、-NHCOCH3、-NHSO2CH3、-N(CH3)CH2CH2N(CH3)2、-CONH-环-C3H5、-CONH-环-C6H11、-CONHCH2CH2N(CH3)CH2Ph、-CH2CH2OH、-OCH2CH2OH、
L是键、-CH2-、-OCH2CH2-、-CO-、-CONH-、-SO2-或-CONHCH2CH2CH2-;
且
R32代表-H、-CH3、-C2H5、-CH(CH3)2、-CH2Ph、-COCH3或-SO2C2H5。
6.选自以下的根据权利要求1所述的化合物:
N-(2-甲基-5-(2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
1-(6-(2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
N-(5-(4-氯-2-(4-(2-(二甲基氨基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(吗啉代甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-吗啉代苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-(吗啉代甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(2-(4-(4-乙酰基哌嗪-1-基)苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-((二甲基氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(吗啉-4-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(甲基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(3-(二甲基氨基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(2-(4-乙酰氨基苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(4-(乙基磺酰基)哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-甲氧基-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(2-(4-(4-乙酰基哌嗪-1-基)苯基)-4-甲氧基-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-甲氧基-2-(4-(吗啉代甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-甲氧基-2-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-甲氧基-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-乙氧基-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-(3-(二甲基氨基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(2-(3-((4-乙酰基哌嗪-1-基)甲基)苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(3-(4-乙基哌嗪-1-基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-(3-(4-乙基哌嗪-1-基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-(吗啉-4-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(6-吗啉代吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(2-(6-(4-乙酰基哌嗪-1-基)吡啶-3-基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(2-吗啉代吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
1-(6-(4-氯-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
N-(5-(4-氯-2-(3-(4-甲基哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(2-(3-(4-乙酰基哌嗪-1-基)苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
3-(3-(3-丙烯酰氨基-4-甲基苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-2-基)-N-(3-(吡咯烷-1-基)丙基)苯甲酰胺;
3-(3-(3-丙烯酰氨基-4-甲基苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-2-基)-N-(1-苄基哌啶-4-基)苯甲酰胺;
3-(3-(3-丙烯酰氨基-4-甲基苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-2-基)-N-环丙基苯甲酰胺;
3-(3-(3-丙烯酰氨基-4-甲基苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-2-基)-N-(3-(苄基(甲基)氨基)丙基)苯甲酰胺;
N-(5-(2-(3-(4-乙酰基哌嗪-1-羰基)苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-(2-甲基-2,7-二氮杂螺[3.5]壬烷-7-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
3-(3-(3-丙烯酰氨基-4-甲基苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-2-基)-N-(3-(4-乙基哌嗪-1-基)丙基)苯甲酰胺;
1-(7-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
N-(5-(4-氯-2-(2-吗啉代嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
1-(7-(4-氯-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
1-(7-(4-氯-2-(3-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
1-(7-(4-氯-2-(6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
N-(5-(4-氯-2-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(4-乙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
1-(7-(4-氯-2-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
1-(7-(4-氯-2-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
1-(7-(4-氯-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
1-(7-(4-氯-2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
1-(7-(4-氯-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
1-(7-(4-氯-2-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-3,4-二氢喹啉-1(2H)-基)丙-2-烯-1-酮;
N-(5-(4-氯-2-(4-(哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
1-(6-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(2-(4-(4-乙酰基哌嗪-1-基)苯基)-4-氯-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(4-((二甲基氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(4-(4-乙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(4-(4-甲基哌嗪-1-羰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(4-(吗啉代甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-氯-2-(4-(3-(二甲基氨基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
N-(5-(4-氯-2-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(4-氯-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(5-氰基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-N-异丙基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
1-(6-(4-乙氧基-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(2-(4-((二甲基氨基)甲基)苯基)-4-乙氧基-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-乙氧基-2-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-乙氧基-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-乙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-乙氧基-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
3-(3-丙烯酰氨基-4-甲基苯基)-N-环己基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
1-(6-(4-甲氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-甲氧基-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-甲氧基-2-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
3-(3-丙烯酰氨基-4-甲基苯基)-N-苄基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
N-(3-乙酰氨基苄基)-3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
1-(6-(4-异丙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-甲氧基-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
1-(6-(4-甲氧基-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)吲哚啉-1-基)丙-2-烯-1-酮;
3-(3-丙烯酰氨基-4-甲基苯基)-N-(4-((4-甲基哌嗪-1-基)甲基)苄基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-N-(2-(吡啶-4-基)乙基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-N-(4-氟苯乙基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
N-((1H-苯并[d]咪唑-2-基)甲基)-3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
N-(2-甲基-5-(2-(2-吗啉代吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺;
N-(2-甲基-5-(2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-N-(3-氨磺酰基苄基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-N-(吡啶-4-基甲基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-N-(吡啶-3-基甲基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-N-((1-甲基哌啶-4-基)甲基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-N-((4-甲基-4H-1,2,4-三唑-3-基)甲基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-N-(2,4-二氟苄基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
N-(4-乙酰氨基苄基)-3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-N-(3-氨甲酰基苄基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸;
2-氯-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)乙酰胺;
(E)-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丁-2-烯酰胺;
N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)乙烯磺酰胺;
(E)-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)-4-(二甲基氨基)丁-2-烯酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸甲酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸乙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸环丁酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸环己酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸环丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸环戊酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸2-甲氧基乙酯;
N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙炔酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸氧杂环丁烷-3-基酯;
(E)-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丁-2-烯酰胺;
(E)-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)-4-(二甲基氨基)丁-2-烯酰胺;
N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)-乙烯磺酰胺;
2-氯-N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)乙酰胺;
N-(5-(4-乙氧基-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
(E)-3-(3-(4-(二甲基氨基)丁-2-烯酰氨基)-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
N-(5-(4-氯-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2,3-二甲基苯基)丙烯酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((二甲基氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
N-(5-(4-氯-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2,3-二甲基苯基)丙烯酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
N-(5-(5-氯-4-甲基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-乙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(2-(二甲基氨基)乙基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
2-(4-(4-乙酰基哌嗪-1-基)苯基)-3-(3-丙烯酰氨基-4-甲基苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(2-吗啉代吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((4-甲基哌嗪-1-基)磺酰基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(2-羟基乙基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(2-(4-甲基哌嗪-1-基)噻唑-5-基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(3-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(6-吗啉代吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(2-吗啉代嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-((二甲基氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(2-羟基乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-(1-甲基哌啶-4-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-5-氟-4-甲基苯基)-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(3-(3-(二甲基氨基)丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-(乙基磺酰基)哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
2-(3-(4-乙酰基哌嗪-1-基)苯基)-3-(3-丙烯酰氨基-4-甲基苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
2-(3-((4-乙酰基哌嗪-1-基)甲基)苯基)-3-(3-丙烯酰氨基-4-甲基苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(3-((二甲基氨基)甲基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
N-(2-甲基-5-(2-(4-(4-甲基哌嗪-1-基)苯基)-5-(三氟甲氧基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺;
2-(3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-基)乙酸;
2-(3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-基)乙酸异丙酯;
N-(5-(5-乙基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
3-(1-丙烯酰基吲哚啉-6-基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
N-(5-(5-乙氧基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(5-(2-(二甲基氨基)-2-氧代乙基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
2-(3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-基)乙酸甲酯;
N-(2-甲基-5-(5-(2-(甲基氨基)-2-氧代乙基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)苯基)丙烯酰胺;
2-(3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-基)乙酸氧杂环丁烷-3-基酯;
3-(3-丙烯酰氨基-4-甲基苯基)-4-甲基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
N-(5-(5-(羟基甲基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(5-异丁酰氨基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
N-(5-(5-乙酰氨基-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2-甲基苯基)丙烯酰胺;
3-(5-丙烯酰氨基-2,4-二甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-(丙烯酰氨基甲基)苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-4-甲基-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-甲基苯基)-2-(4-(2-(二甲基氨基)乙氧基)苯基)-4-甲基-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-4-乙基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-2-甲基苯基)-2-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯;
3-(3-丙烯酰氨基-2-甲基苯基)-2-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯和
3-(3-丙烯酰氨基-2-甲基苯基)-2-(4-(2-(二甲基氨基)乙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-5-甲酸异丙酯
或上述化合物的对映异构体、对映异构体的混合物、非对映异构体、非对映异构体的混合物、互变异构体、水合物、溶剂化物或其药学上可接受的盐。
7.根据权利要求1-6中的任一项所述的化合物,其作为EGFR和Her2的外显子20突变的选择性抑制剂。
8.根据权利要求1-6中的任一项所述的化合物,其用于用作药物。
9.根据权利要求1-6中的任一项所述的化合物,其用于治疗癌症,其中所述癌症具有属于ErbB受体家族的受体的活化突变。
10.用于根据权利要求9的用途所述的化合物,其中所述受体的活化突变是在表皮生长因子受体(EGFR)的外显子20内或在人表皮生长因子受体(HER)的外显子20内的插入,或其中所述受体的活化突变选自Her2 A775_G776insYVMA、EGFR D770_N771insSVD、EGFR H773_V774insNPH、EGFR V769_D770insASV、EGFR P772_H773insPR、EGFR T790M和EGFRT790ML858R。
11.用于根据权利要求9的用途所述的化合物,其中所述癌症选自:乳腺癌、结肠癌、前列腺癌、肺癌、胃癌、卵巢癌、肾癌、肝细胞癌、甲状腺癌、子宫癌、食管癌、鳞状细胞癌、白血病、淋巴瘤、骨肉瘤、黑素瘤、胶质母细胞瘤和神经母细胞瘤。
12.用于根据权利要求9-11中的任一项的用途所述的化合物,其中所述癌症是非小细胞肺癌或乳癌。
13.用于治疗癌症的与至少一种抗癌药物组合的根据权利要求1–12所述的化合物。
14.用于生产式(Ia-1)的化合物的方法,所述方法包括:
步骤A1:在第一钯催化剂和第一碱的存在下,执行吡啶化合物1*与炔烃化合物2a*的第一交叉偶联反应
以得到化合物3*
步骤B1:将化合物3*的三甲基甲硅烷基转化成卤化物如碘化物以得到化合物4*
步骤C1:在第二钯催化剂和第二碱的存在下,执行4*与化合物5*的第二交叉偶联反应
以得到化合物6*
步骤D1:将化合物6*的硝基(NO2)基团还原成伯胺(NH2)基团以得到化合物7*;和
步骤E1:执行化合物7*
与化合物HO-R5或AG-R5的偶联反应以得到式(Ia-1)的产物化合物
用于生产式(Ia-1)的化合物的方法,所述方法包括:
步骤A1:在第一钯催化剂和第一碱的存在下,执行吡啶化合物1*与炔烃化合物2a*的第一交叉偶联反应
以得到化合物3*
步骤D2:将化合物3*的硝基(NO2)基团还原成伯胺(NH2)基团以得到化合物10*
步骤E2:执行化合物10*与化合物HO-R5或AG-R5的偶联反应以得到化合物11*
步骤B2:将化合物11*的三甲基甲硅烷基转化成卤化物如碘化物以得到化合物12*
步骤C2:在第二钯催化剂和第二碱的存在下,执行化合物12*与化合物5*的第二交叉偶联反应以得到式(Ia-1)的产物化合物
用于生产式(Ib)的化合物的方法,所述方法包括:
步骤A3:
i)在第一钯催化剂和第一碱的存在下,执行吡啶化合物1*
与炔烃化合物2b*的第一交叉偶联反应
和
ii)除去在步骤i)以后得到的化合物的保护基PG以得到化合物3b*
步骤E3:执行化合物3b*与化合物HO-R5或AG-R5的偶联反应以得到化合物11b*
步骤B3:将化合物11b*的三甲基甲硅烷基转化成卤化物如碘化物以得到化合物12b*
步骤C3:在第二钯催化剂和第二碱的存在下,执行化合物12b*与化合物5*的第二交叉偶联反应
以得到式(Ib)的产物化合物
X是离去基团且代表Cl、Br、I或OTf;
AG是羧酸的活化基团;
PG是氨基保护基;
TMS是三甲基甲硅烷基;
R′是H或具有1-10个碳原子的烷基链或具有3-12个碳原子的环烷基链,或两个残基R′一起代表从频哪醇衍生出的残基。
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EP18190603.3 | 2018-08-23 | ||
PCT/EP2019/072564 WO2020039060A1 (en) | 2018-08-23 | 2019-08-23 | 4-substituted pyrrolo[2,3-b]pyridine as erbb modulators useful for treating cancer |
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CN106687457A (zh) * | 2014-05-13 | 2017-05-17 | 阿里亚德医药股份有限公司 | 用于激酶抑制的杂芳基化合物 |
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