CN109563092B - 可用作哺乳动物酪氨酸激酶ror1活性的抑制剂的2-苯基咪唑并[4,5-b]吡啶-7-胺衍生物 - Google Patents
可用作哺乳动物酪氨酸激酶ror1活性的抑制剂的2-苯基咪唑并[4,5-b]吡啶-7-胺衍生物 Download PDFInfo
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- 230000000694 effects Effects 0.000 title abstract description 18
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 title description 42
- VUVLESWQADHVCF-UHFFFAOYSA-N 2-phenyl-1h-imidazo[4,5-b]pyridin-7-amine Chemical class N=1C2=C(N)C=CNC2=NC=1C1=CC=CC=C1 VUVLESWQADHVCF-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 238
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 230
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 131
- -1 4-morpholin-4-ylphenyl Chemical group 0.000 claims description 118
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 38
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 35
- 125000005842 heteroatom Chemical group 0.000 claims description 32
- 125000002947 alkylene group Chemical group 0.000 claims description 30
- 208000035475 disorder Diseases 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 14
- 230000003463 hyperproliferative effect Effects 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 210000004072 lung Anatomy 0.000 claims description 6
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 230000002611 ovarian Effects 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 206010029260 Neuroblastoma Diseases 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
- VSEPXUXVUGERQG-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCC)NC1CCN(CC1)C VSEPXUXVUGERQG-UHFFFAOYSA-N 0.000 claims description 2
- YRGTWBPPKALYNE-UHFFFAOYSA-N 6-chloro-N-[1-[[4-(dimethylamino)phenyl]methyl]piperidin-4-yl]-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CC1=CC=C(C=C1)N(C)C YRGTWBPPKALYNE-UHFFFAOYSA-N 0.000 claims 2
- LWANKFQKNFOYNQ-UHFFFAOYSA-N 1-[4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-2,2-dimethylpropan-1-one Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(C(C)(C)C)=O)NC1CCN(CC1)CC LWANKFQKNFOYNQ-UHFFFAOYSA-N 0.000 claims 1
- WUJLHITXKXPGCU-UHFFFAOYSA-N 1-[4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-2-methoxyethanone Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(COC)=O)NC1CCN(CC1)CC WUJLHITXKXPGCU-UHFFFAOYSA-N 0.000 claims 1
- WHSKDYOEPDTWRG-UHFFFAOYSA-N 1-[4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-3-methoxypropan-1-one Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(CCOC)=O)NC1CCN(CC1)CC WHSKDYOEPDTWRG-UHFFFAOYSA-N 0.000 claims 1
- IMQKMTDOLSGFQT-UHFFFAOYSA-N 1-[4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-2,2-dimethylpropan-1-one Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(C(C)(C)C)=O)NC1CCN(CC1)C IMQKMTDOLSGFQT-UHFFFAOYSA-N 0.000 claims 1
- DTMJGOWLEOYHHK-UHFFFAOYSA-N 1-[4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-2-methoxyethanone Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(COC)=O)NC1CCN(CC1)C DTMJGOWLEOYHHK-UHFFFAOYSA-N 0.000 claims 1
- ICVUGJGWLXCRRG-UHFFFAOYSA-N 1-[4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-3-methoxypropan-1-one Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(CCOC)=O)NC1CCN(CC1)C ICVUGJGWLXCRRG-UHFFFAOYSA-N 0.000 claims 1
- PXRICHFMXJUDHJ-UHFFFAOYSA-N 1-[4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanone Chemical compound C(C)(=O)N1CCN(CC1)C1=CC=C(C=C1)C1=NC=2C(=NC=C(C=2NC2CCN(CC2)C)Br)N1 PXRICHFMXJUDHJ-UHFFFAOYSA-N 0.000 claims 1
- AHDLAUYMLNTHNQ-UHFFFAOYSA-N 1-[4-[4-[6-bromo-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanone Chemical compound C(C)(=O)N1CCN(CC1)C1=CC=C(C=C1)C1=NC=2C(=NC=C(C=2NC2CCN(CC2)C(C)C)Br)N1 AHDLAUYMLNTHNQ-UHFFFAOYSA-N 0.000 claims 1
- MIJZHXOKAVUYJX-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-2-methoxyethanone Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(COC)=O)NC1CCN(CC1)CC MIJZHXOKAVUYJX-UHFFFAOYSA-N 0.000 claims 1
- LJCDQHOOMPERKT-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-3-methoxypropan-1-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(CCOC)=O)NC1CCN(CC1)CC LJCDQHOOMPERKT-UHFFFAOYSA-N 0.000 claims 1
- KEZFEGGQVXOIFG-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-2,2-dimethylpropan-1-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(C(C)(C)C)=O)NC1CCN(CC1)C KEZFEGGQVXOIFG-UHFFFAOYSA-N 0.000 claims 1
- QFGOVMREJKIGBX-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-2-methoxyethanone Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(COC)=O)NC1CCN(CC1)C QFGOVMREJKIGBX-UHFFFAOYSA-N 0.000 claims 1
- GIWHKMFZDCBEDY-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-3-methoxypropan-1-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(CCOC)=O)NC1CCN(CC1)C GIWHKMFZDCBEDY-UHFFFAOYSA-N 0.000 claims 1
- YPOCQCQOHRQOEE-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanone Chemical compound C(C)(=O)N1CCN(CC1)C1=CC=C(C=C1)C1=NC=2C(=NC=C(C=2NC2CCN(CC2)C)Cl)N1 YPOCQCQOHRQOEE-UHFFFAOYSA-N 0.000 claims 1
- VORUURRFLOQRRF-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-2-methoxyethanone Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(COC)=O)NC1CCN(CC1)C(C)C VORUURRFLOQRRF-UHFFFAOYSA-N 0.000 claims 1
- YHECLTPFNUMPFY-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanone Chemical compound C(C)(=O)N1CCN(CC1)C1=CC=C(C=C1)C1=NC=2C(=NC=C(C=2NC2CCN(CC2)C(C)C)Cl)N1 YHECLTPFNUMPFY-UHFFFAOYSA-N 0.000 claims 1
- XPIWCPIPCWTDTQ-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[[1-[(1,3,5-trimethylpyrazol-4-yl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanone Chemical compound C(C)(=O)N1CCN(CC1)C1=CC=C(C=C1)C1=NC=2C(=NC=C(C=2NC2CCN(CC2)CC=2C(=NN(C=2C)C)C)Cl)N1 XPIWCPIPCWTDTQ-UHFFFAOYSA-N 0.000 claims 1
- GKNQQFGROVQVIV-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-2-methoxyethanone Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(COC)=O)NC1CCN(CC1)CC1=CC=C(C=C1)OC GKNQQFGROVQVIV-UHFFFAOYSA-N 0.000 claims 1
- KFFYSMUMBZZCAJ-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]-3-methoxypropan-1-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(CCOC)=O)NC1CCN(CC1)CC1=CC=C(C=C1)OC KFFYSMUMBZZCAJ-UHFFFAOYSA-N 0.000 claims 1
- UNIFPEDCYMYENV-UHFFFAOYSA-N 1-[4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanone Chemical compound C(C)(=O)N1CCN(CC1)C1=CC=C(C=C1)C1=NC=2C(=NC=C(C=2NC2CCN(CC2)CC2=CC=C(C=C2)OC)Cl)N1 UNIFPEDCYMYENV-UHFFFAOYSA-N 0.000 claims 1
- IRVCFEHAZMVNHI-UHFFFAOYSA-N 1-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1,4-diazepan-5-one Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCNC(CC1)=O)NC1CCN(CC1)CC IRVCFEHAZMVNHI-UHFFFAOYSA-N 0.000 claims 1
- FVZAORQKNRYOCD-UHFFFAOYSA-N 1-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1,4-diazepan-5-one Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCNC(CC1)=O)NC1CCN(CC1)C FVZAORQKNRYOCD-UHFFFAOYSA-N 0.000 claims 1
- NUYFCPAJLZOVKT-UHFFFAOYSA-N 1-[4-[6-bromo-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1,4-diazepan-5-one Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCNC(CC1)=O)NC1CCN(CC1)C(C)C NUYFCPAJLZOVKT-UHFFFAOYSA-N 0.000 claims 1
- BCEYLPZVJPOAKD-UHFFFAOYSA-N 1-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1,4-diazepan-5-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCNC(CC1)=O)NC1CCN(CC1)CC BCEYLPZVJPOAKD-UHFFFAOYSA-N 0.000 claims 1
- ATKGVJKTZCSCKR-UHFFFAOYSA-N 1-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1,4-diazepan-5-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCNC(CC1)=O)NC1CCN(CC1)C ATKGVJKTZCSCKR-UHFFFAOYSA-N 0.000 claims 1
- BOMHWIQBNPUSOK-UHFFFAOYSA-N 1-[4-[6-chloro-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1,4-diazepan-5-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCNC(CC1)=O)NC1CCN(CC1)C(C)C BOMHWIQBNPUSOK-UHFFFAOYSA-N 0.000 claims 1
- UYWBFCPBENHPPL-UHFFFAOYSA-N 1-[4-[6-chloro-7-[[1-[(1,3,5-trimethylpyrazol-4-yl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1,4-diazepan-5-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCNC(CC1)=O)NC1CCN(CC1)CC=1C(=NN(C=1C)C)C UYWBFCPBENHPPL-UHFFFAOYSA-N 0.000 claims 1
- IDSPOZGNRYWIIE-UHFFFAOYSA-N 1-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1,4-diazepan-5-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCNC(CC1)=O)NC1CCN(CC1)CC1=CC=C(C=C1)OC IDSPOZGNRYWIIE-UHFFFAOYSA-N 0.000 claims 1
- PDXQSBNKMIULGI-UHFFFAOYSA-N 1-benzyl-4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Br)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(Cc2ccccc2)C(=O)C1 PDXQSBNKMIULGI-UHFFFAOYSA-N 0.000 claims 1
- ZIXOOXGIEIKTNK-UHFFFAOYSA-N 1-benzyl-4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-2-one Chemical compound CN1CCC(CC1)Nc1c(Br)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(Cc2ccccc2)C(=O)C1 ZIXOOXGIEIKTNK-UHFFFAOYSA-N 0.000 claims 1
- KDJPGFZXOWMDFM-UHFFFAOYSA-N 1-benzyl-4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Cl)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(Cc2ccccc2)C(=O)C1 KDJPGFZXOWMDFM-UHFFFAOYSA-N 0.000 claims 1
- FPYWTJAWFHKFDQ-UHFFFAOYSA-N 1-benzyl-4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-2-one Chemical compound CN1CCC(CC1)Nc1c(Cl)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(Cc2ccccc2)C(=O)C1 FPYWTJAWFHKFDQ-UHFFFAOYSA-N 0.000 claims 1
- QOBTTXRZNHKDOP-UHFFFAOYSA-N 1-benzyl-4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-2-one Chemical compound COc1ccc(CN2CCC(CC2)Nc2c(Cl)cnc3nc([nH]c23)-c2ccc(cc2)N2CCN(Cc3ccccc3)C(=O)C2)cc1 QOBTTXRZNHKDOP-UHFFFAOYSA-N 0.000 claims 1
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims 1
- AQJRMAALIMUHJE-UHFFFAOYSA-N 2-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound CN1CCC(CC1)C1=NC=2C(=NC=CC=2N)N1 AQJRMAALIMUHJE-UHFFFAOYSA-N 0.000 claims 1
- VWBYLEPWIPOSFJ-UHFFFAOYSA-N 2-[1-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperidin-4-yl]ethanol Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCO)NC1CCN(CC1)CC VWBYLEPWIPOSFJ-UHFFFAOYSA-N 0.000 claims 1
- ZYOHVJAMGSPLKB-UHFFFAOYSA-N 2-[1-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperidin-4-yl]ethanol Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCO)NC1CCN(CC1)C ZYOHVJAMGSPLKB-UHFFFAOYSA-N 0.000 claims 1
- CIMHRDNAUBMDMP-UHFFFAOYSA-N 2-[1-[4-[6-bromo-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperidin-4-yl]ethanol Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCO)NC1CCN(CC1)C(C)C CIMHRDNAUBMDMP-UHFFFAOYSA-N 0.000 claims 1
- LFTCRYVTUYGIDA-UHFFFAOYSA-N 2-[1-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperidin-4-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCO)NC1CCN(CC1)CC LFTCRYVTUYGIDA-UHFFFAOYSA-N 0.000 claims 1
- WUYHKSWVZLEFCC-UHFFFAOYSA-N 2-[1-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperidin-4-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCO)NC1CCN(CC1)C WUYHKSWVZLEFCC-UHFFFAOYSA-N 0.000 claims 1
- KXOBTDKQYYLBOQ-UHFFFAOYSA-N 2-[1-[4-[6-chloro-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperidin-4-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCO)NC1CCN(CC1)C(C)C KXOBTDKQYYLBOQ-UHFFFAOYSA-N 0.000 claims 1
- OKUJHSRCSYXPLA-UHFFFAOYSA-N 2-[1-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperidin-4-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCO)NC1CCN(CC1)CC1=CC=C(C=C1)OC OKUJHSRCSYXPLA-UHFFFAOYSA-N 0.000 claims 1
- OFNAPNIDVVDVHO-UHFFFAOYSA-N 2-[4-(4-benzylpiperazin-1-yl)phenyl]-6-bromo-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound C(C1=CC=CC=C1)N1CCN(CC1)C1=CC=C(C=C1)C1=NC=2C(=NC=C(C=2NC2CCN(CC2)C)Br)N1 OFNAPNIDVVDVHO-UHFFFAOYSA-N 0.000 claims 1
- OOEGHAXQBGAPPC-UHFFFAOYSA-N 2-[4-(4-benzylpiperazin-1-yl)phenyl]-6-chloro-N-(1-ethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound C(C1=CC=CC=C1)N1CCN(CC1)C1=CC=C(C=C1)C1=NC=2C(=NC=C(C=2NC2CCN(CC2)CC)Cl)N1 OOEGHAXQBGAPPC-UHFFFAOYSA-N 0.000 claims 1
- OJCYFXDAOHMSAP-UHFFFAOYSA-N 2-[4-(4-benzylpiperazin-1-yl)phenyl]-6-chloro-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound C(C1=CC=CC=C1)N1CCN(CC1)C1=CC=C(C=C1)C1=NC=2C(=NC=C(C=2NC2CCN(CC2)C)Cl)N1 OJCYFXDAOHMSAP-UHFFFAOYSA-N 0.000 claims 1
- LYJBPKNUPRTDRM-UHFFFAOYSA-N 2-[4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)NC1CCN(CC1)C LYJBPKNUPRTDRM-UHFFFAOYSA-N 0.000 claims 1
- YMYWAGGLVRVPJN-KRWDZBQOSA-N 2-[4-[4-[6-bromo-7-[[(3S)-1-methylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)N[C@@H]1CN(CC1)C YMYWAGGLVRVPJN-KRWDZBQOSA-N 0.000 claims 1
- YLARRPSVQVLGMB-UHFFFAOYSA-N 2-[4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)NC1CCN(CC1)CC YLARRPSVQVLGMB-UHFFFAOYSA-N 0.000 claims 1
- LXQRJNLUBBKDEB-UHFFFAOYSA-N 2-[4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)NC1CCN(CC1)C LXQRJNLUBBKDEB-UHFFFAOYSA-N 0.000 claims 1
- SWDYXQCBAFGBFG-QHCPKHFHSA-N 2-[4-[4-[6-chloro-7-[[(3S)-1-[(4-methoxyphenyl)methyl]pyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)N[C@@H]1CN(CC1)CC1=CC=C(C=C1)OC SWDYXQCBAFGBFG-QHCPKHFHSA-N 0.000 claims 1
- RUSVZFZMXBEFFQ-KRWDZBQOSA-N 2-[4-[4-[6-chloro-7-[[(3S)-1-methylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)N[C@@H]1CN(CC1)C RUSVZFZMXBEFFQ-KRWDZBQOSA-N 0.000 claims 1
- MZAPRFBYMCGYFH-IBGZPJMESA-N 2-[4-[4-[6-chloro-7-[[(3S)-1-propylpyrrolidin-3-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)N[C@@H]1CN(CC1)CCC MZAPRFBYMCGYFH-IBGZPJMESA-N 0.000 claims 1
- ANBUCGOYCRYDMD-UHFFFAOYSA-N 2-[4-[4-[6-chloro-7-[[1-(2,3-dihydro-1-benzofuran-5-ylmethyl)piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)NC1CCN(CC1)CC=1C=CC2=C(CCO2)C=1 ANBUCGOYCRYDMD-UHFFFAOYSA-N 0.000 claims 1
- LRTHOBDIAIQHQJ-UHFFFAOYSA-N 2-[4-[4-[6-chloro-7-[[1-(thiophen-2-ylmethyl)piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)NC1CCN(CC1)CC=1SC=CC=1 LRTHOBDIAIQHQJ-UHFFFAOYSA-N 0.000 claims 1
- CRNQLRKTYIIEDH-UHFFFAOYSA-N 2-[4-[4-[6-chloro-7-[[1-[(1,3,5-trimethylpyrazol-4-yl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)NC1CCN(CC1)CC=1C(=NN(C=1C)C)C CRNQLRKTYIIEDH-UHFFFAOYSA-N 0.000 claims 1
- AOPJFGPPXDRJII-UHFFFAOYSA-N 2-[4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)NC1CCN(CC1)CC1=CC=C(C=C1)OC AOPJFGPPXDRJII-UHFFFAOYSA-N 0.000 claims 1
- KWYDHEREFLEUFW-UHFFFAOYSA-N 2-[4-[4-[6-chloro-7-[[1-[[4-(dimethylamino)phenyl]methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]ethanol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)NC1CCN(CC1)CC1=CC=C(C=C1)N(C)C KWYDHEREFLEUFW-UHFFFAOYSA-N 0.000 claims 1
- PDLCHYCUYSVQCQ-UHFFFAOYSA-N 2-[4-[[6-bromo-2-[3-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]acetonitrile Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)CC#N PDLCHYCUYSVQCQ-UHFFFAOYSA-N 0.000 claims 1
- VKPOGCDMXNARPW-UHFFFAOYSA-N 2-[4-[[6-bromo-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]acetonitrile Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CC#N VKPOGCDMXNARPW-UHFFFAOYSA-N 0.000 claims 1
- LLGIAHSMGKKGAC-UHFFFAOYSA-N 3-[4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propan-1-ol Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCO)NC1CCN(CC1)CC LLGIAHSMGKKGAC-UHFFFAOYSA-N 0.000 claims 1
- UFEQGYMPTQJTRS-UHFFFAOYSA-N 3-[4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propanenitrile Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCC#N)NC1CCN(CC1)CC UFEQGYMPTQJTRS-UHFFFAOYSA-N 0.000 claims 1
- VBNYZKRTYQGUOD-UHFFFAOYSA-N 3-[4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propan-1-ol Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCO)NC1CCN(CC1)C VBNYZKRTYQGUOD-UHFFFAOYSA-N 0.000 claims 1
- KORHWUMSYLWRSL-UHFFFAOYSA-N 3-[4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propanenitrile Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCC#N)NC1CCN(CC1)C KORHWUMSYLWRSL-UHFFFAOYSA-N 0.000 claims 1
- CHJXMHVXHWNDRC-UHFFFAOYSA-N 3-[4-[4-[6-bromo-7-[[1-(cyclopropylmethyl)piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propan-1-ol Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCO)NC1CCN(CC1)CC1CC1 CHJXMHVXHWNDRC-UHFFFAOYSA-N 0.000 claims 1
- TUDCCGOZFFGGGZ-UHFFFAOYSA-N 3-[4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propan-1-ol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCO)NC1CCN(CC1)CC TUDCCGOZFFGGGZ-UHFFFAOYSA-N 0.000 claims 1
- OEVCFOAYXWBIDK-UHFFFAOYSA-N 3-[4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCC#N)NC1CCN(CC1)CC OEVCFOAYXWBIDK-UHFFFAOYSA-N 0.000 claims 1
- BHQJVFJQSUITFW-UHFFFAOYSA-N 3-[4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propan-1-ol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCO)NC1CCN(CC1)C BHQJVFJQSUITFW-UHFFFAOYSA-N 0.000 claims 1
- PJAJKVLOUBBNDU-UHFFFAOYSA-N 3-[4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCC#N)NC1CCN(CC1)C PJAJKVLOUBBNDU-UHFFFAOYSA-N 0.000 claims 1
- WIWNLCZFXMHZHB-UHFFFAOYSA-N 3-[4-[4-[6-chloro-7-[[1-(cyclopropylmethyl)piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propan-1-ol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCO)NC1CCN(CC1)CC1CC1 WIWNLCZFXMHZHB-UHFFFAOYSA-N 0.000 claims 1
- AKGXTXMTIBVDER-UHFFFAOYSA-N 3-[4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCC#N)NC1CCN(CC1)CC1=CC=C(C=C1)OC AKGXTXMTIBVDER-UHFFFAOYSA-N 0.000 claims 1
- SCSYHPDZDHEMKT-UHFFFAOYSA-N 3-[4-[[6-bromo-2-[2-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=C(C=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)CCC#N SCSYHPDZDHEMKT-UHFFFAOYSA-N 0.000 claims 1
- UQLDPTHOMACCIZ-UHFFFAOYSA-N 3-[4-[[6-bromo-2-[4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(C(C)(C)C)=O)NC1CCN(CC1)CCC#N UQLDPTHOMACCIZ-UHFFFAOYSA-N 0.000 claims 1
- TTWQNSILJKRNNV-UHFFFAOYSA-N 3-[4-[[6-bromo-2-[4-[4-(2-ethoxyethyl)-3-oxopiperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(N(CC1)CCOCC)=O)NC1CCN(CC1)CCC#N TTWQNSILJKRNNV-UHFFFAOYSA-N 0.000 claims 1
- OKSVXWCGWMUSOY-UHFFFAOYSA-N 3-[4-[[6-bromo-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CCC#N OKSVXWCGWMUSOY-UHFFFAOYSA-N 0.000 claims 1
- YOLNUTQHFFXWQM-UHFFFAOYSA-N 3-[4-[[6-bromo-2-[4-[4-(4-methoxybutyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCCOC)NC1CCN(CC1)CCC#N YOLNUTQHFFXWQM-UHFFFAOYSA-N 0.000 claims 1
- VRZNRAKUUDFLDR-UHFFFAOYSA-N 3-[4-[[6-chloro-2-[2-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=C(C=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)CCC#N VRZNRAKUUDFLDR-UHFFFAOYSA-N 0.000 claims 1
- IZMVZBHYMNQTNI-UHFFFAOYSA-N 3-[4-[[6-chloro-2-[4-[4-(2,2-dimethylpropanoyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C(C(C)(C)C)=O)NC1CCN(CC1)CCC#N IZMVZBHYMNQTNI-UHFFFAOYSA-N 0.000 claims 1
- MSEPQEJHEJCHQQ-UHFFFAOYSA-N 3-[4-[[6-chloro-2-[4-[4-(2-ethoxyethyl)-3-oxopiperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(N(CC1)CCOCC)=O)NC1CCN(CC1)CCC#N MSEPQEJHEJCHQQ-UHFFFAOYSA-N 0.000 claims 1
- LAOFOFSQWBOVMJ-UHFFFAOYSA-N 3-[4-[[6-chloro-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CCC#N LAOFOFSQWBOVMJ-UHFFFAOYSA-N 0.000 claims 1
- LSKRNZGANYWGBE-UHFFFAOYSA-N 3-[4-[[6-chloro-2-[4-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCO)NC1CCN(CC1)CCC#N LSKRNZGANYWGBE-UHFFFAOYSA-N 0.000 claims 1
- ALMRCJWILDSLIH-UHFFFAOYSA-N 3-[4-[[6-chloro-2-[4-[4-(3-methoxypropyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCOC)NC1CCN(CC1)CCC#N ALMRCJWILDSLIH-UHFFFAOYSA-N 0.000 claims 1
- FLBXFSJNIMALTM-UHFFFAOYSA-N 3-[4-[[6-chloro-2-[4-[4-(4-methoxybutyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]propanenitrile Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCCOC)NC1CCN(CC1)CCC#N FLBXFSJNIMALTM-UHFFFAOYSA-N 0.000 claims 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- KDPCWGNTGYVNSM-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CC(C)(C)N(C)C(C)(C)C3)c2[nH]1 KDPCWGNTGYVNSM-UHFFFAOYSA-N 0.000 claims 1
- TWGSLVMNLRJWQU-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CCN(CC)CC3)c2[nH]1 TWGSLVMNLRJWQU-UHFFFAOYSA-N 0.000 claims 1
- FGBQPPJVEABCNH-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Br)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(CCOC)C(=O)C1 FGBQPPJVEABCNH-UHFFFAOYSA-N 0.000 claims 1
- YAXZETQBZQQBOP-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-propan-2-yloxyethyl)piperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Br)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(CCOC(C)C)C(=O)C1 YAXZETQBZQQBOP-UHFFFAOYSA-N 0.000 claims 1
- LKEBUHQWUZZCIU-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(3-methoxypropyl)piperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Br)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(CCCOC)C(=O)C1 LKEBUHQWUZZCIU-UHFFFAOYSA-N 0.000 claims 1
- HZKALKKYALIHDY-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-methylpiperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Br)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(C)C(=O)C1 HZKALKKYALIHDY-UHFFFAOYSA-N 0.000 claims 1
- HDDKKECXQLDNGW-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CCN(C)CC3)c2[nH]1 HDDKKECXQLDNGW-UHFFFAOYSA-N 0.000 claims 1
- SNQCDZPFFRLHGM-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound COCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CCN(C)CC3)c2[nH]1 SNQCDZPFFRLHGM-UHFFFAOYSA-N 0.000 claims 1
- ZIIUNUGLVPWLLZ-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-propan-2-yloxyethyl)piperazin-2-one Chemical compound CC(C)OCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CCN(C)CC3)c2[nH]1 ZIIUNUGLVPWLLZ-UHFFFAOYSA-N 0.000 claims 1
- CZHDUCLXOFHLDW-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(3-methoxypropyl)piperazin-2-one Chemical compound COCCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CCN(C)CC3)c2[nH]1 CZHDUCLXOFHLDW-UHFFFAOYSA-N 0.000 claims 1
- BFTHGSMVPGPVGM-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-methylpiperazin-2-one Chemical compound CN1CCC(CC1)Nc1c(Br)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(C)C(=O)C1 BFTHGSMVPGPVGM-UHFFFAOYSA-N 0.000 claims 1
- VAKQDVXIZQRQAS-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-2-one Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(NCC1)=O)NC1CCN(CC1)C VAKQDVXIZQRQAS-UHFFFAOYSA-N 0.000 claims 1
- BUWCQARZVUUBKY-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CCN(CC3)C(C)C)c2[nH]1 BUWCQARZVUUBKY-UHFFFAOYSA-N 0.000 claims 1
- IJFVRAHIZIRWDP-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound COCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CCN(CC3)C(C)C)c2[nH]1 IJFVRAHIZIRWDP-UHFFFAOYSA-N 0.000 claims 1
- WFAADALMDWDXNR-UHFFFAOYSA-N 4-[4-[6-bromo-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(3-methoxypropyl)piperazin-2-one Chemical compound COCCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CCN(CC3)C(C)C)c2[nH]1 WFAADALMDWDXNR-UHFFFAOYSA-N 0.000 claims 1
- XEMBAWBOPBYCGW-UHFFFAOYSA-N 4-[4-[6-bromo-7-[[1-(cyclopropylmethyl)piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound COCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Br)c(NC3CCN(CC4CC4)CC3)c2[nH]1 XEMBAWBOPBYCGW-UHFFFAOYSA-N 0.000 claims 1
- DCLOMRKLJBCLFV-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CC(C)(C)N(C)C(C)(C)C3)c2[nH]1 DCLOMRKLJBCLFV-UHFFFAOYSA-N 0.000 claims 1
- NMBXTBMMXPKBBV-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-cyclohexylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound COCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(CC3)C3CCCCC3)c2[nH]1 NMBXTBMMXPKBBV-UHFFFAOYSA-N 0.000 claims 1
- BGKYLIIWQHGWPZ-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(CC)CC3)c2[nH]1 BGKYLIIWQHGWPZ-UHFFFAOYSA-N 0.000 claims 1
- LBRVALQAKWISBL-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Cl)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(CCOC)C(=O)C1 LBRVALQAKWISBL-UHFFFAOYSA-N 0.000 claims 1
- WUIOTDWLHPOQIK-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-propan-2-yloxyethyl)piperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Cl)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(CCOC(C)C)C(=O)C1 WUIOTDWLHPOQIK-UHFFFAOYSA-N 0.000 claims 1
- BWWHFCVIGNXMIV-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(3-methoxypropyl)piperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Cl)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(CCCOC)C(=O)C1 BWWHFCVIGNXMIV-UHFFFAOYSA-N 0.000 claims 1
- RDDAVUADXNCSBU-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-ethylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-methylpiperazin-2-one Chemical compound CCN1CCC(CC1)Nc1c(Cl)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(C)C(=O)C1 RDDAVUADXNCSBU-UHFFFAOYSA-N 0.000 claims 1
- LDDGDFUALCBUFH-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(C)CC3)c2[nH]1 LDDGDFUALCBUFH-UHFFFAOYSA-N 0.000 claims 1
- MLSBZHZXXYSRRK-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound COCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(C)CC3)c2[nH]1 MLSBZHZXXYSRRK-UHFFFAOYSA-N 0.000 claims 1
- NGMNQMVTAWVISC-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-propan-2-yloxyethyl)piperazin-2-one Chemical compound CC(C)OCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(C)CC3)c2[nH]1 NGMNQMVTAWVISC-UHFFFAOYSA-N 0.000 claims 1
- PDOFCYKETOYJMU-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(3-methoxypropyl)piperazin-2-one Chemical compound COCCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(C)CC3)c2[nH]1 PDOFCYKETOYJMU-UHFFFAOYSA-N 0.000 claims 1
- WFNGTCDSGCNQMI-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-methylpiperazin-2-one Chemical compound CN1CCC(CC1)Nc1c(Cl)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(C)C(=O)C1 WFNGTCDSGCNQMI-UHFFFAOYSA-N 0.000 claims 1
- RFLNTIUEWZCNOJ-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-methylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-2-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(NCC1)=O)NC1CCN(CC1)C RFLNTIUEWZCNOJ-UHFFFAOYSA-N 0.000 claims 1
- PGAXQIRFNBGPBI-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(CC3)C(C)C)c2[nH]1 PGAXQIRFNBGPBI-UHFFFAOYSA-N 0.000 claims 1
- FMFJJBCDJXCJLH-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound COCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(CC3)C(C)C)c2[nH]1 FMFJJBCDJXCJLH-UHFFFAOYSA-N 0.000 claims 1
- RKTMXVUMGAMMOK-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-propan-2-yloxyethyl)piperazin-2-one Chemical compound CC(C)OCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(CC3)C(C)C)c2[nH]1 RKTMXVUMGAMMOK-UHFFFAOYSA-N 0.000 claims 1
- UBOQKSALLGODTJ-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(3-methoxypropyl)piperazin-2-one Chemical compound COCCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(CC3)C(C)C)c2[nH]1 UBOQKSALLGODTJ-UHFFFAOYSA-N 0.000 claims 1
- QQPWLHZKPIFUOT-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-propan-2-ylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-2-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(NCC1)=O)NC1CCN(CC1)C(C)C QQPWLHZKPIFUOT-UHFFFAOYSA-N 0.000 claims 1
- DJJODYHYSDOWIM-UHFFFAOYSA-N 4-[4-[6-chloro-7-[(1-propylpiperidin-4-yl)amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCCN1CCC(CC1)Nc1c(Cl)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(CCOCC)C(=O)C1 DJJODYHYSDOWIM-UHFFFAOYSA-N 0.000 claims 1
- SKPZLQVXGLESDV-UHFFFAOYSA-N 4-[4-[6-chloro-7-[[1-(2-methoxyethyl)piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(CCOC)CC3)c2[nH]1 SKPZLQVXGLESDV-UHFFFAOYSA-N 0.000 claims 1
- WJFFHNJRLLUHBI-UHFFFAOYSA-N 4-[4-[6-chloro-7-[[1-(cyclopropylmethyl)piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound COCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(CC4CC4)CC3)c2[nH]1 WJFFHNJRLLUHBI-UHFFFAOYSA-N 0.000 claims 1
- XFDDGKQQMMESJD-UHFFFAOYSA-N 4-[4-[6-chloro-7-[[1-(thiophen-2-ylmethyl)piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(3-methoxypropyl)piperazin-2-one Chemical compound COCCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(Cc4cccs4)CC3)c2[nH]1 XFDDGKQQMMESJD-UHFFFAOYSA-N 0.000 claims 1
- OMALLRPUVCCWDB-UHFFFAOYSA-N 4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-ethoxyethyl)piperazin-2-one Chemical compound CCOCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(Cc4ccc(OC)cc4)CC3)c2[nH]1 OMALLRPUVCCWDB-UHFFFAOYSA-N 0.000 claims 1
- PJCOQQLLFPOOFJ-UHFFFAOYSA-N 4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-methoxyethyl)piperazin-2-one Chemical compound COCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(Cc4ccc(OC)cc4)CC3)c2[nH]1 PJCOQQLLFPOOFJ-UHFFFAOYSA-N 0.000 claims 1
- RQMIVFXQNMATMP-UHFFFAOYSA-N 4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(2-propan-2-yloxyethyl)piperazin-2-one Chemical compound COc1ccc(CN2CCC(CC2)Nc2c(Cl)cnc3nc([nH]c23)-c2ccc(cc2)N2CCN(CCOC(C)C)C(=O)C2)cc1 RQMIVFXQNMATMP-UHFFFAOYSA-N 0.000 claims 1
- ZXJYTKTZYLDNIU-UHFFFAOYSA-N 4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-(3-methoxypropyl)piperazin-2-one Chemical compound COCCCN1CCN(CC1=O)c1ccc(cc1)-c1nc2ncc(Cl)c(NC3CCN(Cc4ccc(OC)cc4)CC3)c2[nH]1 ZXJYTKTZYLDNIU-UHFFFAOYSA-N 0.000 claims 1
- MXEMRHUKLOGUIV-UHFFFAOYSA-N 4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]-1-methylpiperazin-2-one Chemical compound COc1ccc(CN2CCC(CC2)Nc2c(Cl)cnc3nc([nH]c23)-c2ccc(cc2)N2CCN(C)C(=O)C2)cc1 MXEMRHUKLOGUIV-UHFFFAOYSA-N 0.000 claims 1
- ZCQQHBYRBZGAQN-UHFFFAOYSA-N 4-[4-[6-chloro-7-[[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]amino]-1H-imidazo[4,5-b]pyridin-2-yl]phenyl]piperazin-2-one Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(NCC1)=O)NC1CCN(CC1)CC1=CC=C(C=C1)OC ZCQQHBYRBZGAQN-UHFFFAOYSA-N 0.000 claims 1
- BXVDOQPJFRAECN-UHFFFAOYSA-N 4-[[4-[[6-chloro-2-[4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]methyl]-2-methoxyphenol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCO)NC1CCN(CC1)CC1=CC(=C(C=C1)O)OC BXVDOQPJFRAECN-UHFFFAOYSA-N 0.000 claims 1
- UBUKMSQITXOAFH-UHFFFAOYSA-N 4-[[4-[[6-chloro-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-yl]amino]piperidin-1-yl]methyl]-2-methoxyphenol Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CC1=CC(=C(C=C1)O)OC UBUKMSQITXOAFH-UHFFFAOYSA-N 0.000 claims 1
- KCXZESUQQRQZKB-UHFFFAOYSA-N 6-bromo-2-(4-morpholin-4-ylphenyl)-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCOCC1)NC1CCN(CC1)C(C)C KCXZESUQQRQZKB-UHFFFAOYSA-N 0.000 claims 1
- TVNKDDFFZBWKII-UHFFFAOYSA-N 6-bromo-2-[2-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=C(C=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)C TVNKDDFFZBWKII-UHFFFAOYSA-N 0.000 claims 1
- YQHAUSNARAIION-UHFFFAOYSA-N 6-bromo-2-[3-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)C YQHAUSNARAIION-UHFFFAOYSA-N 0.000 claims 1
- MQWXZSQAFLIJIV-UHFFFAOYSA-N 6-bromo-2-[4-(4-ethylpiperazin-1-yl)phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC)NC1CCN(CC1)C MQWXZSQAFLIJIV-UHFFFAOYSA-N 0.000 claims 1
- WXYDPLXFMDONSD-UHFFFAOYSA-N 6-bromo-2-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)C)NC1CCN(CC1)C WXYDPLXFMDONSD-UHFFFAOYSA-N 0.000 claims 1
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- TZVMPMXQNVRUJI-UHFFFAOYSA-N 6-bromo-N-(1-ethylpiperidin-4-yl)-2-[4-[4-[(6-methylpyridin-3-yl)methyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC(=CC=1)C)NC1CCN(CC1)CC TZVMPMXQNVRUJI-UHFFFAOYSA-N 0.000 claims 1
- BPRDGKUVMVRPGF-UHFFFAOYSA-N 6-bromo-N-(1-ethylpiperidin-4-yl)-2-[4-[4-[2-[(2-methylpyrazol-3-yl)amino]ethyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCNC1=CC=NN1C)NC1CCN(CC1)CC BPRDGKUVMVRPGF-UHFFFAOYSA-N 0.000 claims 1
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- HDQUWJRQJWHCHD-UHFFFAOYSA-N 6-bromo-N-(1-methylpiperidin-4-yl)-2-[4-[3-methyl-4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(N(CC1)CC=1SC=CN=1)C)NC1CCN(CC1)C HDQUWJRQJWHCHD-UHFFFAOYSA-N 0.000 claims 1
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- SEXWSOJADLFHLK-UHFFFAOYSA-N 6-bromo-N-(1-methylpiperidin-4-yl)-2-[4-[4-[(6-methylpyridin-2-yl)methyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC(=CC=C1)C)NC1CCN(CC1)C SEXWSOJADLFHLK-UHFFFAOYSA-N 0.000 claims 1
- MDPXLYRCSXTXPP-UHFFFAOYSA-N 6-bromo-N-(1-methylpiperidin-4-yl)-2-[4-[4-[(6-methylpyridin-3-yl)methyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC(=CC=1)C)NC1CCN(CC1)C MDPXLYRCSXTXPP-UHFFFAOYSA-N 0.000 claims 1
- AXGWOAOUWVKAAW-UHFFFAOYSA-N 6-bromo-N-(1-methylpiperidin-4-yl)-2-[4-[4-[2-[(2-methylpyrazol-3-yl)amino]ethyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCNC1=CC=NN1C)NC1CCN(CC1)C AXGWOAOUWVKAAW-UHFFFAOYSA-N 0.000 claims 1
- VVSAGGIOGPUXFT-UHFFFAOYSA-N 6-bromo-N-(1-propan-2-ylpiperidin-4-yl)-2-[4-(4-pyridin-3-ylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C=1C=NC=CC=1)NC1CCN(CC1)C(C)C VVSAGGIOGPUXFT-UHFFFAOYSA-N 0.000 claims 1
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- ZHXFGKJSCYVHBK-UHFFFAOYSA-N 6-bromo-N-(1-propan-2-ylpiperidin-4-yl)-2-[4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=CC=1)NC1CCN(CC1)C(C)C ZHXFGKJSCYVHBK-UHFFFAOYSA-N 0.000 claims 1
- CNGHAQUOQFFUQB-UHFFFAOYSA-N 6-bromo-N-(1-propan-2-ylpiperidin-4-yl)-2-[4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=CC=NC=C1)NC1CCN(CC1)C(C)C CNGHAQUOQFFUQB-UHFFFAOYSA-N 0.000 claims 1
- FLCRLBQOPCQUOU-UHFFFAOYSA-N 6-bromo-N-(1-propan-2-ylpiperidin-4-yl)-2-[4-[4-(pyrimidin-5-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=NC=1)NC1CCN(CC1)C(C)C FLCRLBQOPCQUOU-UHFFFAOYSA-N 0.000 claims 1
- NFHGJTFFTQIYBO-SFHVURJKSA-N 6-bromo-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-(4-pyrazin-2-ylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C1=NC=CN=C1)N[C@@H]1CN(CC1)C NFHGJTFFTQIYBO-SFHVURJKSA-N 0.000 claims 1
- VXBAOXSEBFUAID-IBGZPJMESA-N 6-bromo-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-(4-pyridin-3-ylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C=1C=NC=CC=1)N[C@@H]1CN(CC1)C VXBAOXSEBFUAID-IBGZPJMESA-N 0.000 claims 1
- WNRDZKAMANTMRY-SFHVURJKSA-N 6-bromo-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1SC=CN=1)N[C@@H]1CN(CC1)C WNRDZKAMANTMRY-SFHVURJKSA-N 0.000 claims 1
- MYJMDKHDHYBYLZ-IBGZPJMESA-N 6-bromo-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-[4-(pyrazin-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=CN=C1)N[C@@H]1CN(CC1)C MYJMDKHDHYBYLZ-IBGZPJMESA-N 0.000 claims 1
- PAVNNUMIHVUNAH-NRFANRHFSA-N 6-bromo-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-[4-(pyridin-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=CC=C1)N[C@@H]1CN(CC1)C PAVNNUMIHVUNAH-NRFANRHFSA-N 0.000 claims 1
- WXXDDAKRFQDIFY-NRFANRHFSA-N 6-bromo-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=CC=1)N[C@@H]1CN(CC1)C WXXDDAKRFQDIFY-NRFANRHFSA-N 0.000 claims 1
- HRGPWRUWFHXGEZ-NRFANRHFSA-N 6-bromo-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=CC=NC=C1)N[C@@H]1CN(CC1)C HRGPWRUWFHXGEZ-NRFANRHFSA-N 0.000 claims 1
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- WLQHURZKKFEFGI-UHFFFAOYSA-N 6-bromo-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[2-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=C(C=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)CC1CC1 WLQHURZKKFEFGI-UHFFFAOYSA-N 0.000 claims 1
- AYRZKXFCDLHVGY-UHFFFAOYSA-N 6-bromo-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[3-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)CC1CC1 AYRZKXFCDLHVGY-UHFFFAOYSA-N 0.000 claims 1
- AYXPDJJSEQFNGL-UHFFFAOYSA-N 6-bromo-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[3-methoxy-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)OC)NC1CCN(CC1)CC1CC1 AYXPDJJSEQFNGL-UHFFFAOYSA-N 0.000 claims 1
- XPCNRBGALRRKAX-UHFFFAOYSA-N 6-bromo-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[4-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1SC=CN=1)NC1CCN(CC1)CC1CC1 XPCNRBGALRRKAX-UHFFFAOYSA-N 0.000 claims 1
- DPAZZBPNHKZGNI-UHFFFAOYSA-N 6-bromo-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCC)NC1CCN(CC1)CC1CC1 DPAZZBPNHKZGNI-UHFFFAOYSA-N 0.000 claims 1
- ASZCJLFVAHOIOC-UHFFFAOYSA-N 6-bromo-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CC1CC1 ASZCJLFVAHOIOC-UHFFFAOYSA-N 0.000 claims 1
- ZUIVITULKJZMDX-UHFFFAOYSA-N 6-bromo-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[4-[4-(3-methoxypropyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCOC)NC1CCN(CC1)CC1CC1 ZUIVITULKJZMDX-UHFFFAOYSA-N 0.000 claims 1
- HJNIPXGBOLPGDP-UHFFFAOYSA-N 6-bromo-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=CC=1)NC1CCN(CC1)CC1CC1 HJNIPXGBOLPGDP-UHFFFAOYSA-N 0.000 claims 1
- XAGMWSTUPRQUOV-UHFFFAOYSA-N 6-bromo-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[4-[4-[2-[(2-methylpyrazol-3-yl)amino]ethyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound BrC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCNC1=CC=NN1C)NC1CCN(CC1)CC1CC1 XAGMWSTUPRQUOV-UHFFFAOYSA-N 0.000 claims 1
- XQQLRLUKXPSONV-UHFFFAOYSA-N 6-chloro-2-(4-morpholin-4-ylphenyl)-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCOCC1)NC1CCN(CC1)C(C)C XQQLRLUKXPSONV-UHFFFAOYSA-N 0.000 claims 1
- SUTCFIHWNFFRTN-UHFFFAOYSA-N 6-chloro-2-(4-morpholin-4-ylphenyl)-N-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCOCC1)NC1CCN(CC1)CC=1SC=CC=1 SUTCFIHWNFFRTN-UHFFFAOYSA-N 0.000 claims 1
- QCLYKYCDAKNRBP-UHFFFAOYSA-N 6-chloro-2-(4-morpholin-4-ylphenyl)-N-[1-[(1,3,5-trimethylpyrazol-4-yl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCOCC1)NC1CCN(CC1)CC=1C(=NN(C=1C)C)C QCLYKYCDAKNRBP-UHFFFAOYSA-N 0.000 claims 1
- URIIIZNFULXGHF-UHFFFAOYSA-N 6-chloro-2-[2-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=C(C=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)C URIIIZNFULXGHF-UHFFFAOYSA-N 0.000 claims 1
- BXFYXRCOVANGBE-UHFFFAOYSA-N 6-chloro-2-[2-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=C(C=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)C(C)C BXFYXRCOVANGBE-UHFFFAOYSA-N 0.000 claims 1
- JFXKWHCPFVGNFT-UHFFFAOYSA-N 6-chloro-2-[3-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)C JFXKWHCPFVGNFT-UHFFFAOYSA-N 0.000 claims 1
- QGJYCEGNRNUTPV-UHFFFAOYSA-N 6-chloro-2-[3-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)C(C)C QGJYCEGNRNUTPV-UHFFFAOYSA-N 0.000 claims 1
- ZLFQGHTXGXALGD-UHFFFAOYSA-N 6-chloro-2-[3-methoxy-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)OC)NC1CCN(CC1)C ZLFQGHTXGXALGD-UHFFFAOYSA-N 0.000 claims 1
- FOPXRLQWVIFZFN-UHFFFAOYSA-N 6-chloro-2-[3-methoxy-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)OC)NC1CCN(CC1)C(C)C FOPXRLQWVIFZFN-UHFFFAOYSA-N 0.000 claims 1
- VRCFMFOBMUQCIR-UHFFFAOYSA-N 6-chloro-2-[4-(4-ethylpiperazin-1-yl)phenyl]-N-(1-ethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC)NC1CCN(CC1)CC VRCFMFOBMUQCIR-UHFFFAOYSA-N 0.000 claims 1
- HEFCRIYAXXTDLL-UHFFFAOYSA-N 6-chloro-2-[4-(4-ethylpiperazin-1-yl)phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC)NC1CCN(CC1)C HEFCRIYAXXTDLL-UHFFFAOYSA-N 0.000 claims 1
- QDZJLSYAGCJYDV-UHFFFAOYSA-N 6-chloro-2-[4-(4-ethylpiperazin-1-yl)phenyl]-N-[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC)NC1CCN(CC1)CC1=CC=C(C=C1)OC QDZJLSYAGCJYDV-UHFFFAOYSA-N 0.000 claims 1
- GEIHQJKSWOGWEG-UHFFFAOYSA-N 6-chloro-2-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)C)NC1CCN(CC1)C GEIHQJKSWOGWEG-UHFFFAOYSA-N 0.000 claims 1
- KWUFKWJZWWBFTP-UHFFFAOYSA-N 6-chloro-2-[4-(4-methyl-1,4-diazepan-1-yl)phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)C)NC1CCN(CC1)C(C)C KWUFKWJZWWBFTP-UHFFFAOYSA-N 0.000 claims 1
- PUZCPAMZCDRUEL-UHFFFAOYSA-N 6-chloro-2-[4-(4-methylpiperazin-1-yl)phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound CN1CCC(CC1)Nc1c(Cl)cnc2nc([nH]c12)-c1ccc(cc1)N1CCN(C)CC1 PUZCPAMZCDRUEL-UHFFFAOYSA-N 0.000 claims 1
- PCMLYYUPRUSNCK-UHFFFAOYSA-N 6-chloro-2-[4-(4-methylpiperazin-1-yl)phenyl]-N-[1-[(1,3,5-trimethylpyrazol-4-yl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C)NC1CCN(CC1)CC=1C(=NN(C=1C)C)C PCMLYYUPRUSNCK-UHFFFAOYSA-N 0.000 claims 1
- AEMIRPFLVATCDW-UHFFFAOYSA-N 6-chloro-2-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)S(=O)(=O)C)NC1CCN(CC1)C(C)C AEMIRPFLVATCDW-UHFFFAOYSA-N 0.000 claims 1
- WDEAPJRJONCWFH-UHFFFAOYSA-N 6-chloro-2-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]-N-[1-[(1,3,5-trimethylpyrazol-4-yl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)S(=O)(=O)C)NC1CCN(CC1)CC=1C(=NN(C=1C)C)C WDEAPJRJONCWFH-UHFFFAOYSA-N 0.000 claims 1
- PWKHJVGINJFQQA-UHFFFAOYSA-N 6-chloro-2-[4-(4-pyridin-4-ylpiperazin-1-yl)phenyl]-N-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=NC=C1)NC1CCN(CC1)CC=1SC=CC=1 PWKHJVGINJFQQA-UHFFFAOYSA-N 0.000 claims 1
- MSSDCGSSQPTOPX-UHFFFAOYSA-N 6-chloro-2-[4-[4-(1H-imidazol-5-ylmethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1N=CNC=1)NC1CCN(CC1)C MSSDCGSSQPTOPX-UHFFFAOYSA-N 0.000 claims 1
- PSIRQOLKQOOPBG-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)-1,4-diazepan-1-yl]phenyl]-N-(1-ethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOCC)NC1CCN(CC1)CC PSIRQOLKQOOPBG-UHFFFAOYSA-N 0.000 claims 1
- KVRWSQDYPJFOND-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)-1,4-diazepan-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOCC)NC1CCN(CC1)C KVRWSQDYPJFOND-UHFFFAOYSA-N 0.000 claims 1
- SGERKGYIRFWKPI-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)-1,4-diazepan-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOCC)NC1CCN(CC1)C(C)C SGERKGYIRFWKPI-UHFFFAOYSA-N 0.000 claims 1
- IKIVSPFXJCZECP-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)-1,4-diazepan-1-yl]phenyl]-N-[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOCC)NC1CCN(CC1)CC1=CC=C(C=C1)OC IKIVSPFXJCZECP-UHFFFAOYSA-N 0.000 claims 1
- CFEHPSPPBAUGAB-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl]-N-(1-ethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCC)NC1CCN(CC1)CC CFEHPSPPBAUGAB-UHFFFAOYSA-N 0.000 claims 1
- GSOYMHNKIMKGQV-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCC)NC1CCN(CC1)C(C)C GSOYMHNKIMKGQV-UHFFFAOYSA-N 0.000 claims 1
- WNPUMVJBJLDRPC-IBGZPJMESA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCC)N[C@@H]1CN(CC1)C WNPUMVJBJLDRPC-IBGZPJMESA-N 0.000 claims 1
- DGUKUEUDDHCZHF-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl]-N-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCC)NC1CCN(CC1)CC=1SC=CC=1 DGUKUEUDDHCZHF-UHFFFAOYSA-N 0.000 claims 1
- RHHNZDALDDJQIJ-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl]-N-[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCC)NC1CCN(CC1)CC1=CC=C(C=C1)OC RHHNZDALDDJQIJ-UHFFFAOYSA-N 0.000 claims 1
- SVMCTJTVRPIVIG-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)piperidin-1-yl]phenyl]-N-(1-ethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCOCC)NC1CCN(CC1)CC SVMCTJTVRPIVIG-UHFFFAOYSA-N 0.000 claims 1
- DMSFIYIVAKMRCA-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)piperidin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCOCC)NC1CCN(CC1)C DMSFIYIVAKMRCA-UHFFFAOYSA-N 0.000 claims 1
- UNWSTNAKWQQMRD-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-ethoxyethyl)piperidin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCOCC)NC1CCN(CC1)C(C)C UNWSTNAKWQQMRD-UHFFFAOYSA-N 0.000 claims 1
- YHWPHZGIRAIVKI-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOC)NC1CCN(CC1)C YHWPHZGIRAIVKI-UHFFFAOYSA-N 0.000 claims 1
- XCNSQDSXLOBAIL-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOC)NC1CCN(CC1)C(C)C XCNSQDSXLOBAIL-UHFFFAOYSA-N 0.000 claims 1
- ZRMUEKBQMHFECF-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]phenyl]-N-[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOC)NC1CCN(CC1)CC1=CC=C(C=C1)OC ZRMUEKBQMHFECF-UHFFFAOYSA-N 0.000 claims 1
- VOOZLRLBMINRKO-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)-2-methylpiperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1C(CN(CC1)CCOC)C)NC1CCN(CC1)C VOOZLRLBMINRKO-UHFFFAOYSA-N 0.000 claims 1
- KQNYPDFFAVVYDA-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)-3-methylpiperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(N(CC1)CCOC)C)NC1CCN(CC1)C KQNYPDFFAVVYDA-UHFFFAOYSA-N 0.000 claims 1
- RXCFMJZMIMSJSL-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CC(N(C(C1)(C)C)C)(C)C RXCFMJZMIMSJSL-UHFFFAOYSA-N 0.000 claims 1
- YQXRPBUTIMWHRF-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)C YQXRPBUTIMWHRF-UHFFFAOYSA-N 0.000 claims 1
- NRFGFWOBLKFHKR-FQEVSTJZSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-[(3S)-1-propylpyrrolidin-3-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)N[C@@H]1CN(CC1)CCC NRFGFWOBLKFHKR-FQEVSTJZSA-N 0.000 claims 1
- FVLZPVGLELQEQR-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CC=1SC=CC=1 FVLZPVGLELQEQR-UHFFFAOYSA-N 0.000 claims 1
- JJNSNJBPHCWTGW-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-[1-[(1,3,5-trimethylpyrazol-4-yl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CC=1C(=NN(C=1C)C)C JJNSNJBPHCWTGW-UHFFFAOYSA-N 0.000 claims 1
- AIICTRAGSPFWIC-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-N-[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CC1=CC=C(C=C1)OC AIICTRAGSPFWIC-UHFFFAOYSA-N 0.000 claims 1
- MRQFPOCQZWFSQO-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)piperidin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCOC)NC1CCN(CC1)C MRQFPOCQZWFSQO-UHFFFAOYSA-N 0.000 claims 1
- SBCONHAWKOQLMD-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-methoxyethyl)piperidin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCOC)NC1CCN(CC1)C(C)C SBCONHAWKOQLMD-UHFFFAOYSA-N 0.000 claims 1
- OSBDZJCMDUCBOW-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-propan-2-yloxyethyl)-1,4-diazepan-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOC(C)C)NC1CCN(CC1)C(C)C OSBDZJCMDUCBOW-UHFFFAOYSA-N 0.000 claims 1
- STJOEBXLGDGKAP-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-propan-2-yloxyethyl)piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC(C)C)NC1CCN(CC1)C(C)C STJOEBXLGDGKAP-UHFFFAOYSA-N 0.000 claims 1
- SAULSODSAIDEAP-UHFFFAOYSA-N 6-chloro-2-[4-[4-(2-propan-2-yloxyethyl)piperazin-1-yl]phenyl]-N-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC(C)C)NC1CCN(CC1)CC=1SC=CC=1 SAULSODSAIDEAP-UHFFFAOYSA-N 0.000 claims 1
- UJSLUIJPTWIFAA-UHFFFAOYSA-N 6-chloro-2-[4-[4-(3-methoxypropyl)-2-methylpiperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1C(CN(CC1)CCCOC)C)NC1CCN(CC1)C UJSLUIJPTWIFAA-UHFFFAOYSA-N 0.000 claims 1
- GTUUJUVTMPCLHK-UHFFFAOYSA-N 6-chloro-2-[4-[4-(3-methoxypropyl)-3-methylpiperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(N(CC1)CCCOC)C)NC1CCN(CC1)C GTUUJUVTMPCLHK-UHFFFAOYSA-N 0.000 claims 1
- PCNPZDABLPLKIT-UHFFFAOYSA-N 6-chloro-2-[4-[4-(3-methoxypropyl)piperazin-1-yl]phenyl]-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCOC)NC1CC(N(C(C1)(C)C)C)(C)C PCNPZDABLPLKIT-UHFFFAOYSA-N 0.000 claims 1
- VEKFFLABYKULQR-UHFFFAOYSA-N 6-chloro-2-[4-[4-(3-methoxypropyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCOC)NC1CCN(CC1)C VEKFFLABYKULQR-UHFFFAOYSA-N 0.000 claims 1
- NFSBAIBZXYQTPP-UHFFFAOYSA-N 6-chloro-2-[4-[4-(3-methoxypropyl)piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCOC)NC1CCN(CC1)C(C)C NFSBAIBZXYQTPP-UHFFFAOYSA-N 0.000 claims 1
- WYPZVGXBNRNUMT-UHFFFAOYSA-N 6-chloro-2-[4-[4-(3-methoxypropyl)piperazin-1-yl]phenyl]-N-(1-propylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCOC)NC1CCN(CC1)CCC WYPZVGXBNRNUMT-UHFFFAOYSA-N 0.000 claims 1
- DWKQYQGIIVPNAA-UHFFFAOYSA-N 6-chloro-2-[4-[4-(4-methoxybutyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCCOC)NC1CCN(CC1)C DWKQYQGIIVPNAA-UHFFFAOYSA-N 0.000 claims 1
- DNJVCLXOWCKKKD-UHFFFAOYSA-N 6-chloro-2-[4-[4-(4-methoxybutyl)piperazin-1-yl]phenyl]-N-[1-[(4-methoxyphenyl)methyl]piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCCOC)NC1CCN(CC1)CC1=CC=C(C=C1)OC DNJVCLXOWCKKKD-UHFFFAOYSA-N 0.000 claims 1
- MBCRHGCSSFSUSB-UHFFFAOYSA-N 6-chloro-2-[4-[4-(furan-2-ylmethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1OC=CC=1)NC1CCN(CC1)C MBCRHGCSSFSUSB-UHFFFAOYSA-N 0.000 claims 1
- OKOFTLAFEWRZHC-UHFFFAOYSA-N 6-chloro-2-[4-[4-(furan-2-ylmethyl)piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1OC=CC=1)NC1CCN(CC1)C(C)C OKOFTLAFEWRZHC-UHFFFAOYSA-N 0.000 claims 1
- OXGMXISHEQKJAV-UHFFFAOYSA-N 6-chloro-2-[4-[4-(furan-3-ylmethyl)piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=COC=C1)NC1CCN(CC1)C OXGMXISHEQKJAV-UHFFFAOYSA-N 0.000 claims 1
- WOJGIMUPSPVREE-UHFFFAOYSA-N 6-chloro-2-[4-[4-[(1-methylimidazol-2-yl)methyl]piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1N(C=CN=1)C)NC1CCN(CC1)C WOJGIMUPSPVREE-UHFFFAOYSA-N 0.000 claims 1
- WBNODXGGGWDMAM-UHFFFAOYSA-N 6-chloro-2-[4-[4-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C(=NOC=1C)C)NC1CCN(CC1)C WBNODXGGGWDMAM-UHFFFAOYSA-N 0.000 claims 1
- YBKXEBHQRQPFBB-UHFFFAOYSA-N 6-chloro-2-[4-[4-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C(=NOC=1C)C)NC1CCN(CC1)C(C)C YBKXEBHQRQPFBB-UHFFFAOYSA-N 0.000 claims 1
- TYNPYOZATZLOPL-UHFFFAOYSA-N 6-chloro-2-[4-[4-[(5-methylfuran-2-yl)methyl]piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1OC(=CC=1)C)NC1CCN(CC1)C TYNPYOZATZLOPL-UHFFFAOYSA-N 0.000 claims 1
- LQHFHJJDBWROAT-UHFFFAOYSA-N 6-chloro-2-[4-[4-[(6-methylpyridin-3-yl)methyl]piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC(=CC=1)C)NC1CCN(CC1)C(C)C LQHFHJJDBWROAT-UHFFFAOYSA-N 0.000 claims 1
- BQARTOCGXJETEQ-UHFFFAOYSA-N 6-chloro-2-[4-[4-[2-(2-methoxyethoxy)ethyl]piperazin-1-yl]phenyl]-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCCOC)NC1CCN(CC1)C BQARTOCGXJETEQ-UHFFFAOYSA-N 0.000 claims 1
- SQFIZGBGEOMQEO-UHFFFAOYSA-N 6-chloro-2-[4-[4-[2-(2-methoxyethoxy)ethyl]piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCCOC)NC1CCN(CC1)C(C)C SQFIZGBGEOMQEO-UHFFFAOYSA-N 0.000 claims 1
- IPXMTQJRYMJGMO-FQEVSTJZSA-N 6-chloro-2-[4-[4-[2-(2-methoxyethoxy)ethyl]piperazin-1-yl]phenyl]-N-[(3S)-1-methylpyrrolidin-3-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCCOC)N[C@@H]1CN(CC1)C IPXMTQJRYMJGMO-FQEVSTJZSA-N 0.000 claims 1
- AYZOGYLNLIPESK-UHFFFAOYSA-N 6-chloro-2-[4-[4-[2-(2-methoxyethoxy)ethyl]piperazin-1-yl]phenyl]-N-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCCOC)NC1CCN(CC1)CC=1SC=CC=1 AYZOGYLNLIPESK-UHFFFAOYSA-N 0.000 claims 1
- QJWDCGIKMMZCDM-UHFFFAOYSA-N 6-chloro-2-[4-[4-[2-(2-methoxyethoxy)ethyl]piperazin-1-yl]phenyl]-N-[1-(thiophen-3-ylmethyl)piperidin-4-yl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCCOC)NC1CCN(CC1)CC1=CSC=C1 QJWDCGIKMMZCDM-UHFFFAOYSA-N 0.000 claims 1
- JDWMFUMPVQJXHW-UHFFFAOYSA-N 6-chloro-2-[4-[4-[2-[(2-methylpyrazol-3-yl)amino]ethyl]piperazin-1-yl]phenyl]-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCNC1=CC=NN1C)NC1CC(N(C(C1)(C)C)C)(C)C JDWMFUMPVQJXHW-UHFFFAOYSA-N 0.000 claims 1
- RNBHSRVYLXYXRD-UHFFFAOYSA-N 6-chloro-2-[4-[4-[2-[(2-methylpyrazol-3-yl)amino]ethyl]piperazin-1-yl]phenyl]-N-(1-propan-2-ylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCNC1=CC=NN1C)NC1CCN(CC1)C(C)C RNBHSRVYLXYXRD-UHFFFAOYSA-N 0.000 claims 1
- ARLUDKLRJOVBPH-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[2-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=C(C=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)CC ARLUDKLRJOVBPH-UHFFFAOYSA-N 0.000 claims 1
- CKDXUJCUINYOPX-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[3-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)CC CKDXUJCUINYOPX-UHFFFAOYSA-N 0.000 claims 1
- LETPJZLLOYONNP-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[3-methoxy-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)OC)NC1CCN(CC1)CC LETPJZLLOYONNP-UHFFFAOYSA-N 0.000 claims 1
- GDXUFFSXTNSHNR-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)S(=O)(=O)C)NC1CCN(CC1)CC GDXUFFSXTNSHNR-UHFFFAOYSA-N 0.000 claims 1
- RHJWOYLISFHRRL-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-(4-pyridin-3-ylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C=1C=NC=CC=1)NC1CCN(CC1)CC RHJWOYLISFHRRL-UHFFFAOYSA-N 0.000 claims 1
- NQPWSWPGABSWMS-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[3-methyl-4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(N(CC1)CC=1SC=CN=1)C)NC1CCN(CC1)CC NQPWSWPGABSWMS-UHFFFAOYSA-N 0.000 claims 1
- XJDQNDJFZBAFGS-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1SC=CN=1)NC1CCN(CC1)CC XJDQNDJFZBAFGS-UHFFFAOYSA-N 0.000 claims 1
- SVKLBKRNPNRHBM-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(1,3-thiazol-4-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1N=CSC=1)NC1CCN(CC1)CC SVKLBKRNPNRHBM-UHFFFAOYSA-N 0.000 claims 1
- XSIJCQKSTOSQQC-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(1,3-thiazol-5-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=CN=CS1)NC1CCN(CC1)CC XSIJCQKSTOSQQC-UHFFFAOYSA-N 0.000 claims 1
- COZDFRLACVPJQQ-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(1H-imidazol-5-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1N=CNC=1)NC1CCN(CC1)CC COZDFRLACVPJQQ-UHFFFAOYSA-N 0.000 claims 1
- LFSICOZUGMOWMU-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOC)NC1CCN(CC1)CC LFSICOZUGMOWMU-UHFFFAOYSA-N 0.000 claims 1
- XZWNASMUDOIKBI-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(2-methoxyethyl)-3-methylpiperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(N(CC1)CCOC)C)NC1CCN(CC1)CC XZWNASMUDOIKBI-UHFFFAOYSA-N 0.000 claims 1
- MTIYSFLBYVRNEB-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CC MTIYSFLBYVRNEB-UHFFFAOYSA-N 0.000 claims 1
- IJOUOSFRWYSLJQ-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(2-methoxyethyl)piperidin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCC(CC1)CCOC)NC1CCN(CC1)CC IJOUOSFRWYSLJQ-UHFFFAOYSA-N 0.000 claims 1
- UCACOCSGFRJFSH-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(2-propan-2-yloxyethyl)-1,4-diazepan-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOC(C)C)NC1CCN(CC1)CC UCACOCSGFRJFSH-UHFFFAOYSA-N 0.000 claims 1
- GIMFHAMFBHEKMA-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(2-propan-2-yloxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC(C)C)NC1CCN(CC1)CC GIMFHAMFBHEKMA-UHFFFAOYSA-N 0.000 claims 1
- ABXMPFSWEBFGEL-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(3-methoxypropyl)-2-methylpiperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1C(CN(CC1)CCCOC)C)NC1CCN(CC1)CC ABXMPFSWEBFGEL-UHFFFAOYSA-N 0.000 claims 1
- GGADWMPTJYGWFX-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(3-methoxypropyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCOC)NC1CCN(CC1)CC GGADWMPTJYGWFX-UHFFFAOYSA-N 0.000 claims 1
- VVKPZBMCWTUUHE-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(4-methoxybutyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCCOC)NC1CCN(CC1)CC VVKPZBMCWTUUHE-UHFFFAOYSA-N 0.000 claims 1
- ALMHXBQBCGZULB-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(pyrazin-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=CN=C1)NC1CCN(CC1)CC ALMHXBQBCGZULB-UHFFFAOYSA-N 0.000 claims 1
- AUXTZKWWZJJDJD-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(pyridin-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=CC=C1)NC1CCN(CC1)CC AUXTZKWWZJJDJD-UHFFFAOYSA-N 0.000 claims 1
- ZEEYKJBEZGYTBW-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=CC=1)NC1CCN(CC1)CC ZEEYKJBEZGYTBW-UHFFFAOYSA-N 0.000 claims 1
- WSWRXTXMHIWRIW-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=CC=NC=C1)NC1CCN(CC1)CC WSWRXTXMHIWRIW-UHFFFAOYSA-N 0.000 claims 1
- IITXQVIPUIIZRO-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-[(1-methylimidazol-2-yl)methyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1N(C=CN=1)C)NC1CCN(CC1)CC IITXQVIPUIIZRO-UHFFFAOYSA-N 0.000 claims 1
- SHPSFGHDGUXFPK-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-[(5-methylpyridin-2-yl)methyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=C(C=C1)C)NC1CCN(CC1)CC SHPSFGHDGUXFPK-UHFFFAOYSA-N 0.000 claims 1
- REJBREWCQGGJMV-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-[(6-methylpyridin-2-yl)methyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC(=CC=C1)C)NC1CCN(CC1)CC REJBREWCQGGJMV-UHFFFAOYSA-N 0.000 claims 1
- HMKYMZAWSOXGEZ-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-[2-(2-methoxyethoxy)ethyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCCOC)NC1CCN(CC1)CC HMKYMZAWSOXGEZ-UHFFFAOYSA-N 0.000 claims 1
- FNPCOLKRDZJCBD-UHFFFAOYSA-N 6-chloro-N-(1-ethylpiperidin-4-yl)-2-[4-[4-[2-[(2-methylpyrazol-3-yl)amino]ethyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCNC1=CC=NN1C)NC1CCN(CC1)CC FNPCOLKRDZJCBD-UHFFFAOYSA-N 0.000 claims 1
- YRYBPJVUNLTVAK-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-(4-morpholin-4-ylphenyl)-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCOCC1)NC1CCN(CC1)C YRYBPJVUNLTVAK-UHFFFAOYSA-N 0.000 claims 1
- BAVQRSQJJOSUTI-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)S(=O)(=O)C)NC1CCN(CC1)C BAVQRSQJJOSUTI-UHFFFAOYSA-N 0.000 claims 1
- OZDVJTLVEOIHPW-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-(4-pyrazin-2-ylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C1=NC=CN=C1)NC1CCN(CC1)C OZDVJTLVEOIHPW-UHFFFAOYSA-N 0.000 claims 1
- OMMYUMBGSWCOTH-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-(4-pyridin-3-ylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C=1C=NC=CC=1)NC1CCN(CC1)C OMMYUMBGSWCOTH-UHFFFAOYSA-N 0.000 claims 1
- YHCNVUQOPHAWOV-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-(4-pyridin-4-ylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=NC=C1)NC1CCN(CC1)C YHCNVUQOPHAWOV-UHFFFAOYSA-N 0.000 claims 1
- OSXANEMXTYCZMN-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[2-methyl-4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1C(CN(CC1)CC=1SC=CN=1)C)NC1CCN(CC1)C OSXANEMXTYCZMN-UHFFFAOYSA-N 0.000 claims 1
- AQXLRBHVMWPVJO-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[3-methyl-4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(N(CC1)CC=1SC=CN=1)C)NC1CCN(CC1)C AQXLRBHVMWPVJO-UHFFFAOYSA-N 0.000 claims 1
- FTAMYYDPGWZJFG-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CC(N(CC1)CC=1C=NC=CC=1)C)NC1CCN(CC1)C FTAMYYDPGWZJFG-UHFFFAOYSA-N 0.000 claims 1
- BICIKZTZQHORGA-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1SC=CN=1)NC1CCN(CC1)C BICIKZTZQHORGA-UHFFFAOYSA-N 0.000 claims 1
- JPZZHDYWVWRUKN-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-(1,3-thiazol-5-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=CN=CS1)NC1CCN(CC1)C JPZZHDYWVWRUKN-UHFFFAOYSA-N 0.000 claims 1
- TVTXZIXAMINWKY-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-(2-propan-2-yloxyethyl)-1,4-diazepan-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CCC1)CCOC(C)C)NC1CCN(CC1)C TVTXZIXAMINWKY-UHFFFAOYSA-N 0.000 claims 1
- NUSCHSGGAVXPGO-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-(2-propan-2-yloxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC(C)C)NC1CCN(CC1)C NUSCHSGGAVXPGO-UHFFFAOYSA-N 0.000 claims 1
- WBBPICNSUDDOGS-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-(pyrazin-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=CN=C1)NC1CCN(CC1)C WBBPICNSUDDOGS-UHFFFAOYSA-N 0.000 claims 1
- KZBSJLMTTIZSSH-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-(pyridin-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=CC=C1)NC1CCN(CC1)C KZBSJLMTTIZSSH-UHFFFAOYSA-N 0.000 claims 1
- ZMJJHVNFLIVGNR-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=CC=NC=C1)NC1CCN(CC1)C ZMJJHVNFLIVGNR-UHFFFAOYSA-N 0.000 claims 1
- SJYRUWSONWETDG-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-(pyrimidin-5-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=NC=1)NC1CCN(CC1)C SJYRUWSONWETDG-UHFFFAOYSA-N 0.000 claims 1
- GYRLUEPSIIGCES-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-[(5-methylpyridin-2-yl)methyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=C(C=C1)C)NC1CCN(CC1)C GYRLUEPSIIGCES-UHFFFAOYSA-N 0.000 claims 1
- FFGOJOQEXHEGPT-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-[(6-methylpyridin-2-yl)methyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC(=CC=C1)C)NC1CCN(CC1)C FFGOJOQEXHEGPT-UHFFFAOYSA-N 0.000 claims 1
- IAHXYZDYJYDHMJ-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-[(6-methylpyridin-3-yl)methyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC(=CC=1)C)NC1CCN(CC1)C IAHXYZDYJYDHMJ-UHFFFAOYSA-N 0.000 claims 1
- DOFBKJHYGBDYAR-UHFFFAOYSA-N 6-chloro-N-(1-methylpiperidin-4-yl)-2-[4-[4-[2-[(2-methylpyrazol-3-yl)amino]ethyl]piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCNC1=CC=NN1C)NC1CCN(CC1)C DOFBKJHYGBDYAR-UHFFFAOYSA-N 0.000 claims 1
- PYMVWDWQLSCWKL-UHFFFAOYSA-N 6-chloro-N-(1-propan-2-ylpiperidin-4-yl)-2-[4-(4-pyridin-4-ylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=NC=C1)NC1CCN(CC1)C(C)C PYMVWDWQLSCWKL-UHFFFAOYSA-N 0.000 claims 1
- CARVAHIGPYIZHN-UHFFFAOYSA-N 6-chloro-N-(1-propan-2-ylpiperidin-4-yl)-2-[4-[4-(pyrazin-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=CN=C1)NC1CCN(CC1)C(C)C CARVAHIGPYIZHN-UHFFFAOYSA-N 0.000 claims 1
- SGHIOEQZALNJEI-UHFFFAOYSA-N 6-chloro-N-(1-propan-2-ylpiperidin-4-yl)-2-[4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=CC=1)NC1CCN(CC1)C(C)C SGHIOEQZALNJEI-UHFFFAOYSA-N 0.000 claims 1
- DTDWXIAGCTZUQL-UHFFFAOYSA-N 6-chloro-N-(1-propan-2-ylpiperidin-4-yl)-2-[4-[4-(pyrimidin-5-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=NC=1)NC1CCN(CC1)C(C)C DTDWXIAGCTZUQL-UHFFFAOYSA-N 0.000 claims 1
- NQBGWJXMEXIBPF-MHZLTWQESA-N 6-chloro-N-[(3S)-1-[(4-methoxyphenyl)methyl]pyrrolidin-3-yl]-2-[4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=CC=1)N[C@@H]1CN(CC1)CC1=CC=C(C=C1)OC NQBGWJXMEXIBPF-MHZLTWQESA-N 0.000 claims 1
- RPEOUTHPYKJYGP-NRFANRHFSA-N 6-chloro-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-[4-(pyridin-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=CC=C1)N[C@@H]1CN(CC1)C RPEOUTHPYKJYGP-NRFANRHFSA-N 0.000 claims 1
- OYQIUYUKBNVIFY-NRFANRHFSA-N 6-chloro-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=CC=1)N[C@@H]1CN(CC1)C OYQIUYUKBNVIFY-NRFANRHFSA-N 0.000 claims 1
- PLUWCIOEVHKWLS-NRFANRHFSA-N 6-chloro-N-[(3S)-1-methylpyrrolidin-3-yl]-2-[4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=CC=NC=C1)N[C@@H]1CN(CC1)C PLUWCIOEVHKWLS-NRFANRHFSA-N 0.000 claims 1
- PCYHQXGKFBKOTO-QHCPKHFHSA-N 6-chloro-N-[(3S)-1-propylpyrrolidin-3-yl]-2-[4-[4-(pyridin-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=NC=CC=C1)N[C@@H]1CN(CC1)CCC PCYHQXGKFBKOTO-QHCPKHFHSA-N 0.000 claims 1
- WTMBPIIIVBRQCY-QHCPKHFHSA-N 6-chloro-N-[(3S)-1-propylpyrrolidin-3-yl]-2-[4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1C=NC=CC=1)N[C@@H]1CN(CC1)CCC WTMBPIIIVBRQCY-QHCPKHFHSA-N 0.000 claims 1
- PWDHJXAUBLPPHJ-QHCPKHFHSA-N 6-chloro-N-[(3S)-1-propylpyrrolidin-3-yl]-2-[4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC1=CC=NC=C1)N[C@@H]1CN(CC1)CCC PWDHJXAUBLPPHJ-QHCPKHFHSA-N 0.000 claims 1
- VXIXHGOMVTWVAK-UHFFFAOYSA-N 6-chloro-N-[1-(2,3-dihydro-1-benzofuran-5-ylmethyl)piperidin-4-yl]-2-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)S(=O)(=O)C)NC1CCN(CC1)CC=1C=CC2=C(CCO2)C=1 VXIXHGOMVTWVAK-UHFFFAOYSA-N 0.000 claims 1
- FAAQLMPETOFLGU-UHFFFAOYSA-N 6-chloro-N-[1-(2,3-dihydro-1-benzofuran-5-ylmethyl)piperidin-4-yl]-2-[4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOCC)NC1CCN(CC1)CC=1C=CC2=C(CCO2)C=1 FAAQLMPETOFLGU-UHFFFAOYSA-N 0.000 claims 1
- NIEALMKHDQFTCL-UHFFFAOYSA-N 6-chloro-N-[1-(2,3-dihydro-1-benzofuran-5-ylmethyl)piperidin-4-yl]-2-[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCOC)NC1CCN(CC1)CC=1C=CC2=C(CCO2)C=1 NIEALMKHDQFTCL-UHFFFAOYSA-N 0.000 claims 1
- VVCLRXRQRJTHMG-UHFFFAOYSA-N 6-chloro-N-[1-(2-methoxyethyl)piperidin-4-yl]-2-[4-[4-(3-methoxypropyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CCCOC)NC1CCN(CC1)CCOC VVCLRXRQRJTHMG-UHFFFAOYSA-N 0.000 claims 1
- JUIUZXYEDLTXSM-UHFFFAOYSA-N 6-chloro-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[2-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=C(C=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)CC1CC1 JUIUZXYEDLTXSM-UHFFFAOYSA-N 0.000 claims 1
- DUJWQDHTERYLLH-UHFFFAOYSA-N 6-chloro-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[3-fluoro-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)F)NC1CCN(CC1)CC1CC1 DUJWQDHTERYLLH-UHFFFAOYSA-N 0.000 claims 1
- KIQALQOVNFJPGW-UHFFFAOYSA-N 6-chloro-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[3-methoxy-4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC(=C(C=C1)N1CCN(CC1)CCOC)OC)NC1CCN(CC1)CC1CC1 KIQALQOVNFJPGW-UHFFFAOYSA-N 0.000 claims 1
- IXLRJELUWODTRV-UHFFFAOYSA-N 6-chloro-N-[1-(cyclopropylmethyl)piperidin-4-yl]-2-[4-[4-(1,3-thiazol-2-ylmethyl)piperazin-1-yl]phenyl]-1H-imidazo[4,5-b]pyridin-7-amine Chemical compound ClC=1C(=C2C(=NC=1)NC(=N2)C1=CC=C(C=C1)N1CCN(CC1)CC=1SC=CN=1)NC1CCN(CC1)CC1CC1 IXLRJELUWODTRV-UHFFFAOYSA-N 0.000 claims 1
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Abstract
式(I′)或(I″)的化合物或其药学上可接受的盐。该化合物是哺乳动物激酶活性,包括ROR1酪氨酸激酶活性的抑制剂,可用于治疗与此类活性相关的失调。
Description
发明领域
本发明涉及某些2-苯基咪唑并[4,5-b]吡啶-7-胺衍生物,它们可用作哺乳动物激酶活性,包括ROR1酪氨酸激酶活性的抑制剂。本发明进一步涉及某些2-苯基咪唑并[4,5-b]吡啶-7-胺衍生物,其用于疗法,例如,用于治疗其中人激酶活性的调节是有益的医学病症。这种病症的实例包括各种过度增殖性疾病,例如,血液肿瘤如慢性淋巴细胞性白血病(chronic lymphocytic leukemia)(CLL)、急性骨髓性白血病(acute myeloid leukemia)(AML)、急性淋巴母细胞性白血病(acute lymphoblastic leukemia)(ALL)或套细胞淋巴瘤,以及实体肿瘤如肺、卵巢、乳腺或胰腺肿瘤。这种病症的其他实例包括肥胖相关的代谢并发症,自身免疫疾病和炎性病症。
发明背景
慢性淋巴细胞性白血病(CLL)起源于B淋巴细胞,B淋巴细胞在活化和成熟阶段不同,其来源于具有不同免疫球蛋白重链可变(IgVH)基因突变的经历过抗原的B细胞(Chiorazzi N et al.,N.Engl.J.Med.,2005,352,804-15)。与具有未突变基因的患者相比,具有突变IgVH基因的患者具有更好的预后(Damle RN et al.,Blood 1999,94,1840-7;Hamblin TJ et al.,Blood,1999,94,1848-54)。全球基因表达谱研究已经揭示了,在突变和未突变的白血病B细胞中部分区别但总体重叠的表达谱,表明了共同的表型(Klein U etal.,J.Exp.Med.,2001,194,1625-38;Rosenwald A et al.,J.Exp.Med.,2001,194,1639-47)。
基因表达谱研究表明在CLL细胞中孤儿受体酪氨酸激酶(RTK)ROR1的43.8倍的增加(Klein U et al.,J.Exp.Med.,2001,194,1625-38)。ROR1是与肌肉特异性激酶(MUSK)和Trk神经营养因子(Trk neurotrophin)受体相关的孤儿受体的RTK家族成员(Glass DJ,etal.,Cell,1996,85,513-23;Masiakowski P et al.,J.Biol.Chem.,1992,267,26181-90;Valenzuela DM et al.,Neuron,1995,15,573-84)。ROR受体是参与信号转导、细胞-细胞相互作用、调节细胞增殖、分化、细胞代谢和存活的细胞表面受体(Masiakowski P et al.,Biol.Chem.,1992,267,26181-90;Yoda A et al.,J.Recept.Signal Transduct.Res.,2003,23,1-15)。它们在不同物种例如人、小鼠、果蝇和秀丽隐杆线虫(C.elegans)之间在进化上具有高度保守性,表现出重要的生物学功能。
人ROR1基因具有2814bp的编码区,具有预测的937个氨基酸的序列和105kDa的蛋白质大小,包括Ig-样结构域、富含半胱氨酸的结构域、kringle结构域、酪氨酸激酶结构域和富含脯氨酸的结构域(Yoda A et al.,J.Recept.Signal Transduct.Res.,2003,23,1-15)。ROR1位于染色体区1p31.3上(http://www.ensembl.org),该染色体区是在血液恶性肿瘤中染色体畸变不常见的区。人ROR1在心脏、肺和肾脏中以基因水平表达,但在胎盘、胰腺和骨骼肌中较少表达(Reddy UR et al.,Oncogene,1996,13,1555-9)。重要的是,正常成年人组织和器官中几乎完全没有ROR1蛋白表达。ROR1最初从成神经细胞瘤细胞系克隆(Masiakowski P et al.,J.Biol.Chem.,1992,267,26181-90),且随后将缺少整个细胞外结构域但包含跨膜结构域的较短形式从胎脑库(fetal brain library)中分离。已经报道了在胎儿和成年人中枢神经系统、人类白血病、淋巴瘤细胞系和源自神经外胚层的多种人类癌症中的截短的ROR1(t-Ror1)基因(Reddy UR et al.,Oncogene,1996,13,1555-9)。还描述了包含内含子7的短部分的外显子1-7的较短转录物,预测长度为393个氨基酸,分子量为44kDa(Ensembl ID;ENSG00000185483)。
慢性淋巴细胞性白血病(CLL)患者的基因谱和蛋白质表达研究已显示ROR1的表达增加,而来自健康供体的成熟白细胞不表达该蛋白(DaneshManesh,A H et al.,Int.J.Cancer,2008,123,1190-5)。在CLL细胞中用siRNA使ROR1沉默导致凋亡,而来自正常供体的B细胞的siRNA处理没有导致凋亡(Choudhury,A et al.,Brit.J.Haematol.,2010,151,327-35)。
急性骨髓性白血病(AML)干细胞(CD34+)可能潜在地解释了对许多细胞毒性药物的耐性。在体外测定中,对抗ROR1的嵌合抗体(UC99961)以剂量依赖性方式抑制ROR1+AML干细胞而不是ROR-AML细胞且不是正常CD34+干细胞的集落形成。结果表明,靶向ROR可能代表根除AML以及潜在的其他难治性癌症-干细胞驱动的恶性肿瘤中恶性干细胞的重要组成部分(Balaian L et al,Blood,ASH Annual Meeting)2012,Abstract 2560)。在急性淋巴母细胞性白血病(ALL)中,ROR1以与导致AKT、ERK和MEK的激活的前B细胞受体(pre-BCR)信号转导途径平衡的方式上调调节。siRNA转染诱导ALL细胞的生长受损和凋亡(Bicocca V etal,Cancer Cell,22,656-667,2012)。
人乳腺癌细胞,但不是正常乳腺上皮细胞,也表达ROR1。激素受体阴性肿瘤患者以及细胞分化程度低的患者(即预后差的患者)的ROR1表达强度较高。ROR1的沉默损害了人乳腺癌细胞在体外生长和在免疫缺陷小鼠中的生长。结果支持了这样一个概念,ROR1在乳腺癌中具有生物学和临床意义,可能是疗法的潜在靶点(Zang S et al,PLoS One,7(3):e31127,2012)。
在人肺腺癌细胞中,ROR1过度表达。ROR1激酶活性在增殖性PI3K/AKT和凋亡性p38信号转导之间维持有利的促存活平衡,这部分地是通过ROR1激酶依赖性src激活以及激酶非依赖性地维持EGFR/ERBB3磷酸化和PI3K激活。ROR1敲低在体外和体内有效抑制肺癌细胞的生长,不管EGFR状态如何,包括对EGFR酪氨酸激酶抑制剂吉非替尼具有抗性的那些细胞。这些数据也表明ROR1在肺癌中的重要生物学作用和用于靶向疗法的结构(Yamaguchi etal,Cancer Cell,21,348-361,2012)。意外的是,CLL细胞表现出ERBB2的过度表达和src/PI3K、AKT/mTOR/CREB的磷酸化。该工作(见下文)中描述的ROR1酪氨酸激酶抑制剂在CLL细胞凋亡之前使ROR1/src/PI3K/AKT/mTOR/CREB脱磷酸化(自身的未公布的观测结果)。
在另一项研究中,许多实体肿瘤组织(肺、卵巢、胰腺)表达ROR1,但正常的细胞对应物不表达。ROR1表达与高级组织学和AKT和CREB的激活相关。使用shRNA使ROR1沉默诱导胰腺和卵巢癌细胞系的凋亡和ROR1蛋白以及活化的AKT和CREB的下调(Zhan S et al,American Journal of Pathology,181:1903-1910,2012)。
已经表明黑素瘤细胞表达ROR1。在凋亡之前ROR1siRNA诱导mRNA和蛋白质水平的ROR1下调。通过ROR1定向单克隆抗体靶向黑素瘤细胞的ROR1诱导了显著凋亡,不需要免疫细胞或补体。由抗体诱导的凋亡程度在细胞系之间变化(Hodjat-Farsangi M et al,PLoSOne,8,e61167,2013)。此外,最近已经表明,ROR1在3T3-L1细胞中的脂肪形成和葡萄糖体内平衡中起重要作用(Sanchez-Solana,B,Laborda,J and Baladron,V,MolecularEndocrinology 26:110–127,2012)。因此,调控WNT途径(例如通过调节ROR1)来改变脂肪细胞的组成可能构成对抗肥胖相关代谢并发症的有吸引力的药物开发目标(Christodoulides,C,Lagathu,C,Sethi,J K and Vidal-Puig,A,TrendsEndocrinol.Metab.,2009 Jan;20(1):16-24)。
上述数据用于说明调节ROR1活性以治疗失调和疾病的有效性,所述失调和疾病不仅包括慢性淋巴细胞性白血病(CLL),还包括其他血液恶性肿瘤以及实体肿瘤和肥胖相关的代谢并发症。
ROR1的抗体抑制剂已在文献中描述;例如PCT Int.Appl.WO2011079902。然而,本领域中没有已知的ROR1的小分子抑制剂。取代的咪唑并[4,5-b]吡啶化合物是本领域熟知的,例如,见于PCT Int.Appl.WO2003045929,WO2004016270,WO2004016611,WO2006066913,WO2006066914,WO2006080821,WO2006125958,WO2007028135,WO2007072017,WO2007083978,WO2008121063,WO2008121064,WO2009001021,WO2009111277,WO2011066211,WO2013116291,Wang,T.et al.Bioorg.Med.Chem.Lett.,2012,22(5),2063-2069,Bavetsias,V.et al.J.Med.Chem.,2010,53,5213-5228和Bavetsias,V.etal.J.Med.Chem.,2012,55,8721-8734。但是,之前没有表明这种化合物能够调节ROR1活性。
发明概述
第一方面是式(I′)或(I″)的化合物
或其药学上可接受的盐,其中
x是0至4的整数;
每个Ra独立地选自C1-C3烷基;
m是1或2;
R1是C1-C6烷基,C3-C6环烷基,C3-C6环烷基-C1-C6烷基,C1-C6烷基-C3-C6环烷基,C1-C6烷氧基-C1-C6烷基,氰基-C1-C6烷基,或式(II)的部分
环A是苯基或5或6元杂芳基;
g是0至3的整数;
每个R1a独立地选自C1-C6烷基,R1bO和R1cR1dN;
每个R1b独立地选自H和C1-C6烷基;
每个R1c独立地选自H和C1-C6烷基;
每个R1d独立地选自H和C1-C6烷基;
或与环A的相邻原子连接的两个R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环;
R2是Cl或Br;
p是0至3的整数;
每个R3独立地选自C1-C6烷基;
y是0至3的整数;
Rb选自卤素,C1-C3烷基和C1-C3烷氧基;
Z是N或CH;
W是>Q-R4,-O-或-N(R5)C(O)-;
Q是N或CH;
当W是>Q-R4或-O-时,n是1或2;
当W是-N(R5)C(O)-时,n是0或1;
R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,R4cC(O),氰基-C1-C6烷基或式(III)的部分
每个q独立地选自1、2、3和4;
r是1或2;
h是0至3的整数;
Y是直接键或C(O);
L是直接键,C1-C4亚烷基或-L1-L2-;
L1是直接键或C1-C4亚烷基;
L2是C(O)或NH;
R4a是H或C1-C6烷基;
R4b是C1-C6烷基;
R4c是C1-C6烷基;
R4d是C1-C6烷基;
环B选自苯基和5或6元杂芳基;
R5是H,C1-C6烷基,R5a[O(CH2)u]v,或式(IV)的部分
R5a是H或C1-C6烷基;
每个u独立地选自1、2、3和4;
v是1或2;
M是直接键或C1-C4亚烷基;
环C选自苯基和5或6元杂芳基;
R5b是C1-C6烷基;和
j是0至3的整数。
另一方面是用于疗法的式(I′)或(I″)化合物。
又一方面是式(I′)或(I″)的化合物或其药学上可接受的盐,其用作哺乳动物,优选人中酪氨酸激酶ROR1活性的抑制剂。
另一方面是药物组合物,其包含式(I′)或(I″)化合物或其药学上可接受的盐,和任选的药学上可接受的赋形剂。
另一方面是式(I′)或(I″)的化合物或其药学上可接受的盐,其用于治疗其中调节哺乳动物例如人酪氨酸激酶ROR1活性有益的病症或失调,例如恶性过度增殖性失调,肥胖相关的代谢并发症,自身免疫疾病或炎性病症。
一方面是式(I′)或(I″)的化合物或其药学上可接受的盐,其用于治疗恶性过度增殖性失调,肥胖相关的代谢并发症,自身免疫疾病或炎性病症。
另一方面是式(I′)或(I″)化合物在制备药物中的用途,所述药物用于治疗其中调节哺乳动物例如人酪氨酸激酶ROR1活性有益的病症或失调,例如恶性过度增殖性失调,肥胖相关的代谢并发症,自身免疫疾病或炎性病症。
恶性过度增殖性失调的实例包括但不限于血液肿瘤,例如慢性淋巴细胞性白血病(CLL)、急性骨髓性白血病(AML)、急性淋巴母细胞性白血病(ALL)或套细胞淋巴瘤,以及实体肿瘤如肺、卵巢、乳腺或胰腺肿瘤。
另一方面是治疗其中调节哺乳动物例如人酪氨酸激酶ROR1活性有益的病症或失调的方法,所述病症或失调例如恶性过度增殖性失调,肥胖相关的代谢并发症,自身免疫疾病或炎性病症,所述方法是通过给予需要这样的治疗的哺乳动物,优选人治疗有效量的式(I′)或(I″)化合物。
发明详细描述
除非另有说明,否则本文使用的任何术语应赋予其常规含义。例如,单独或作为基团的一部分的术语“烷基”包括通式CnH2n+1的直链或支链烷基。
术语“C1-C6烷基”是指具有1、2、3、4、5或6个碳原子的烷基部分。
术语“亚烷基”是指衍生自相应烷烃的饱和二价基团。例如,亚甲基是C1亚烷基。
术语“C3-C6环烷基”是指环中具有3、4、5或6个碳原子的环烷基部分,即环丙基,环丁基,环戊基或环己基。
术语“C3-C6环烷基-C1-C6烷基”是指被C3-C6环烷基取代的C1-C6烷基。这种部分的实例是下式的环丙基甲基:
术语“C1-C6烷基-C3-C6环烷基”是指被C1-C6烷基取代的C3-C6环烷基。这种部分的实例是4-甲基环己基。
术语“C1-C6烷氧基-C1-C6烷基”是指被C1-C6烷氧基取代的C1-C6烷基。实例是2-甲氧基乙基,具有下式:
术语“氰基-C1-C6烷基”是指被氰基取代的C1-C6烷基。实例是2-氰基乙基,具有下式:
术语“直接键”是指化合物的两个部分之间的共价键。
术语“杂原子”优选指N,O或S。
术语“5或6元杂芳基”是指在环中含有5或6个原子的杂芳基。
术语“卤素”是指F、Cl、Br或I,特别是F、Cl或Br。
术语“羟基”是指式-OH的基团。
“任选的”或“任选地”是指随后描述的事件或情况可能发生但不是必须发生,并且该描述包括事件或情况发生的情形以及不发生的情形。
“药学上可接受的”是指可用于制备药物组合物的事物,该药物组合物通常是安全的、无毒的,且非生物学及其他方面所不期望,并且包括对于兽用和人类药物用途可接受的事物。
术语“赋形剂”是指药学上可接受的化学物质,例如药学领域的普通技术人员已知的用于帮助给予药用剂的那些。它是可用于制备药物组合物的化合物,其通常是安全的、无毒的,且非生物学及其他方面所不期望,并且包括对于兽用和人类药物用途可接受的赋形剂。示例性的赋形剂包括粘合剂、表面活性剂、稀释剂、崩解剂、抗粘附剂和润滑剂。
“治疗有效量”是指当给予受试者来治疗疾病状态时足以实现疾病状态的这种治疗的化合物的量。“治疗有效量”将根据化合物、所治疗的疾病状态、所治疗疾病的严重程度,受试者的年龄和相对健康、给药途径和形式、主治医疗或兽医从业者的判断等而变化。
如本文所用,术语“治疗(treatment)”或“治疗的(treating)”是获得有益或期望结果包括临床结果的方法。有益或期望的临床结果可以包括但不限于一个或多个症状或病症的减轻或改善、疾病程度的减少、疾病状态的稳定化(即不恶化)、预防疾病传播、延迟或减缓疾病进展、疾病状态的改善或缓解,以及好转(部分或全部),无论是可检测或不可检测的。该术语还可以意味着与没有该治疗的预期生存期相比延长生存期。
术语哺乳动物是指人或任何哺乳动物,例如,灵长类动物、农场动物、宠物动物或实验动物。这些动物的实例有猴、母牛、羊、马、猪、狗、猫、兔、小鼠、大鼠等。优选地,哺乳动物是人。
术语“恶性过度增殖性失调”是指由异常和不受控制的细胞分裂引起的任何恶性生长或肿瘤;它可能通过淋巴系统或血流扩散到身体的其他部分,并且包括实体肿瘤和血源性肿瘤二者。示例性癌症包括肾上腺皮质癌、AIDS相关癌症、AIDS相关淋巴瘤、肛门癌、肛门直肠癌、阑尾癌、儿童小脑星形细胞瘤、儿童大脑星形细胞瘤、基底细胞癌、胆道癌、肝外胆管癌、肝内胆管癌、泌尿膀胱癌、骨和关节癌、骨肉瘤和恶性纤维组织细胞瘤、脑肿瘤、脑干胶质瘤、小脑星形细胞瘤、大脑星形细胞瘤/恶性胶质瘤、室管膜瘤、成神经管细胞瘤、视觉通路和下丘脑神经胶质瘤、乳腺癌、支气管腺瘤/类癌、神经系统癌症、神经系统淋巴瘤、中枢神经系统癌症、中枢神经系统淋巴瘤、子宫颈癌、儿童期癌症、慢性淋巴细胞性白血病、慢性骨髓性白血病、慢性骨髓增殖性失调、结肠癌、结肠直肠癌、皮肤T细胞淋巴瘤、淋巴样肿瘤、蕈样肉芽肿、Sezary综合征、子宫内膜癌、食道癌、颅外生殖细胞瘤、性腺外生殖细胞瘤、眼癌、视网膜母细胞瘤、胆囊癌、胃(胃的)癌、胃肠类癌肿瘤、胃肠道间质瘤(GIST)、生殖细胞瘤、卵巢生殖细胞瘤、妊娠滋养细胞瘤胶质瘤、头颈癌、肝细胞癌(肝癌)、霍奇金(Hodgkin’s)淋巴瘤、咽下癌、眼癌(ocular cancer)、卡波西(Kaposi’s)肉瘤、肾癌、喉癌、急性淋巴母细胞性白血病、急性骨髓性白血病、毛细胞白血病、唇和口腔癌、肺癌、非小细胞肺癌、小细胞肺癌、非霍奇金淋巴瘤、原发性中枢神经系统淋巴瘤、瓦尔登斯特伦(Waldenstrom's)巨球蛋白血症、眼内(眼)黑素瘤、Merkel细胞癌、恶性间皮瘤、转移性鳞状颈癌、舌癌、多发性内分泌肿瘤综合征、骨髓增生异常综合征、骨髓增生异常/骨髓增殖疾病、鼻咽癌、成神经细胞瘤、口癌、口腔癌、口咽癌、卵巢癌、卵巢上皮癌、卵巢低恶性潜在肿瘤、胰腺癌、胰岛细胞胰腺癌、鼻旁窦和鼻腔癌、甲状旁腺癌、阴茎癌、嗜铬细胞瘤、松果体母细胞瘤和幕上原始神经外胚层肿瘤、垂体瘤、浆细胞肿瘤/多发性骨髓瘤、胸膜肺母细胞瘤、前列腺癌、横纹肌肉瘤、唾液腺癌、肿瘤的尤文氏(Ewing's)肉瘤家族、软组织肉瘤、子宫癌、子宫肉瘤、皮肤癌(非黑素瘤)、皮肤癌(黑素瘤)、小肠癌、鳞状细胞癌、睾丸癌、咽喉癌、胸腺瘤(thymoma)、胸腺瘤和胸腺癌(thymoma and thymic carcinoma)、甲状腺癌、肾盂和输尿管和其他泌尿器官的移行细胞癌、妊娠滋养细胞肿瘤、尿道癌、阴道癌、外阴癌和威尔姆氏(Wilm's)肿瘤。
术语“自身免疫失调”是指身体对身体中通常存在的物质和组织不适当的免疫反应(自身免疫)引起的任何失调。这种反应可能限于某些器官或涉及不同地方的特定组织。示例性自身免疫失调是急性播散性脑脊髓炎(ADEM)、艾迪生(Addison's)病、无丙种球蛋白血症、斑秃、肌萎缩性侧索硬化、强直性脊柱炎、抗磷脂综合征、抗合成酶综合征、特应性变态反应、特应性皮炎、自身免疫再生障碍性贫血、自身免疫心肌病、自身免疫肠病、自身免疫溶血性贫血、自身免疫肝炎、自身免疫内耳疾病、自身免疫淋巴细胞增殖综合征、自身免疫周围神经病、自身免疫胰腺炎、自身免疫多内分泌综合征、自身免疫黄体酮性皮炎、自身免疫血小板减少性紫癜、自身免疫荨麻疹、自身免疫葡萄膜炎、Balo疾病/Balo同心硬化(concentric sclerosis)、病、Berger's病、Bickerstaff's脑炎、Blau综合征、大疱性类天疱疮、Castleman's病、乳糜泻、查加斯(Chagas)病、慢性炎性脱髓鞘性多发性神经病、慢性复发性多病灶性骨髓炎、慢性阻塞性肺病、Churg-Strauss综合征、瘢痕性类天疱疮、柯根(Cogan)综合征、冷凝集素病、补体成分2缺乏症、接触性皮炎、颅动脉炎、CREST综合征、克罗恩(Crohn's)病(两种特发性炎性肠病“IBD”之一)、Cushing's综合征、皮肤白细胞破碎性脉管炎、Dego's病、Dercum's病、疱疹样皮炎、皮肌炎、1型糖尿病、弥漫性皮肤系统性硬化症、Dressler's综合征、药物诱导的狼疮、盘状红斑狼疮、湿疹、子宫内膜异位症、附着点炎相关性关节炎、嗜曙红细胞筋膜炎、嗜曙红细胞性胃肠炎、获得性大疱性表皮松解症、结节性红斑、胎儿成红细胞增多病、原发性混合型冷球蛋白血症、伊万氏(Evan's)综合征、进行性肌肉骨化症(fibrodysplasia ossificans progressive)、纤维化肺泡炎(或特发性肺纤维化)、胃炎、胃肠类天疱疮、肾小球肾炎、古德帕斯特(Goodpasture's)综合征、格雷夫斯(Graves')病、格林-巴利综合征(Guillain-Barré syndrome)(GBS)、Hashimoto's脑病、Hashimoto's甲状腺炎、Henoch-Schonlein紫癜、妊娠疱疹(又称妊娠类天疱疮)、化脓性汗腺炎、Hughes-Stovin综合征、低丙球蛋白血症、特发性炎性脱髓鞘病、特发性肺纤维化、特发性血小板减少性紫癜(idiopathic thrombocytopenic purpura)、IgA肾病、包涵体肌炎、慢性炎性脱髓鞘多神经病、间质性膀胱炎、青少年特发性关节炎(又称青少年类风湿性关节炎)、Kawasaki's病、Lambert-Eaton肌无力综合征、白细胞破碎性脉管炎、扁平苔藓、硬化性苔藓、线性IgA病(LAD)、类狼疮肝炎(又称自身免疫肝炎)、红斑狼疮、Majeed综合征、Ménière's病、显微镜下多血管炎(microscopic polyangiitis)、混合性结缔组织病、硬斑病、Mucha-Habermann病(又称急性苔藓痘疮样糠疹(pityriasis lichenoides etvarioliformis acuta))、多发性硬化、重症肌无力、肌炎、发作性睡病、视神经脊髓炎(还称作Devic氏病)、神经肌强直、眼瘢痕性类天疱疮、斜视眼肌阵挛综合征、Ord氏(Ord's)甲状腺炎、回纹型风湿症、PANDAS(与链球菌有关的儿科自身免疫神经精神失调)、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿(PNH)、Parry Romberg综合征、Parsonage-Turner综合征、扁平部睫状体炎、寻常型天疱疮、恶性贫血、静脉周围性脑脊髓炎、POEMS综合征、结节性多动脉炎、风湿性多肌痛、多肌炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、进行性炎性神经病、牛皮癣、牛皮癣性关节炎、坏疽性脓皮病(pyoderma gangrenosum)、纯红细胞发育不良、拉斯穆森(Rasmussen's)脑炎、雷诺(Raynaud)现象、复发性多软骨炎、赖特(Reiter's)综合征、不宁腿综合征、腹膜后纤维化、类风湿性关节炎、风湿热、结节病、精神分裂症、施密特(Schmidt)综合征(APS的另一种形式)、施奈茨勒(Schnitzler)综合征、巩膜炎、硬皮病、血清病、综合征、脊柱关节病、僵人综合征(stiff person syndrome)、亚急性细菌性心内膜炎(SBE)、Susac's综合征、Sweet's综合征、交感性眼炎、系统性红斑狼疮、Takayasu's动脉炎、颞动脉炎(也称作“巨细胞动脉炎”)、血小板减少症、Tolosa-Hunt综合征、横贯性脊髓炎、溃疡性结肠炎(两种特发性炎性肠病“IBD”之一)、与混合型结缔组织疾病不同的未分化结缔组织疾病、未分化的脊柱关节病、荨麻疹性脉管炎、脉管炎、白癜风和韦格纳(Wegener's)肉芽肿病。
术语“炎性失调”是指与炎症相关的病理状态,通常由白细胞浸润引起。炎性失调可能是急性或慢性的。示例性的炎性失调包括炎性皮肤疾病,包括但不限于牛皮癣和特应性皮炎,系统性硬皮病和硬化症,与炎性肠病(IBD)相关的反应(如克罗恩病和溃疡性结肠炎),缺血性再灌注失调,包括手术组织再灌注损伤,心肌缺血病症如心肌梗塞,心动停止,心脏手术后的再灌注和经皮腔内冠状动脉血管成形术后的缩窄,中风,和腹部主动脉瘤,继发于中风的脑水肿,颅外伤,低血容性休克,窒息,成人呼吸窘迫综合征,急性肺损伤,白塞氏(Behcet's)病,皮肌炎,多肌炎,多发性硬化症(MS),皮炎,脑膜炎,脑炎,葡萄膜炎,骨关节炎,狼疮性肾炎,自身免疫疾病如类风湿性关节炎(RA),综合征,脉管炎,涉及白细胞渗出的疾病,中枢神经系统(CNS)炎症性失调,继发于败血病或外伤的多器官损伤综合征,酒精性肝炎,细菌性肺炎,抗原-抗体复合物介导的疾病包括肾小球性肾炎,败血症,结节病,对组织或器官移植的免疫病理性反应,肺的炎症,包括胸膜炎,肺泡炎,脉管炎,肺炎,慢性支气管炎,支气管扩张,弥漫性全细支气管炎,超敏性肺炎,特发性肺纤维化(IPF)和囊性纤维化等。
术语“与肥胖相关的代谢并发症”通常是指由于肥胖引起的代谢并发症,通常称为代谢综合征,该综合征的特征在于血浆脂质失调(致动脉粥样化血脂异常)、升高的血压、升高的血浆葡萄糖和血栓形成前状态。该代谢综合征的临床后果是例如冠心病和中风、2型糖尿病及其并发症、脂肪肝和胆固醇性胆结石。
式(I′)和(I″)的化合物是位置异构体(区域异构体),其在下文中将由通式(I)表示。
其中含有Z和W的环处于对位(式(I′))或间位(式(I″))。因此,除非另有说明或从上下文中显而易见,否则对式(I)化合物的任何提及应解释为同等地指区域异构体(I′)和(I″)。然而,在一些实施方案中,该化合物如式(I′)所表示。在一些其他实施方案中,该化合物如式(I″)所表示。
应该认识到,存在式(I)化合物的三种互变异构体。式(I)化合物应理解为不仅包括3H-咪唑并[4,5-b]吡啶形式,还包括互变异构的1H-咪唑并[4,5-b]吡啶形式。
和互变异构的4H-咪唑并[4,5-b]吡啶形式
因此,任何明确提及的3H-咪唑并[4,5-b]吡啶也包括相应的1H-咪唑并[4,5-b]吡啶和4H-咪唑并[4,5-b]吡啶互变异构体。
此外,除非另有说明或从上下文中显而易见,否则对式(I)化合物的任何提及均应解释为同等地指其任何下述实施方案。
在式(I)化合物中,m为1或2。在一些实施方案中,m为1。在一些进一步的实施方案中,m为2,即式(I)的化合物可以通过式(Ia)表示
其中R1、R2、每个R3、每个Ra、每个Rb、Z、W、n、p、x和y如本文定义。
式(I)化合物中,x是选自0、1、2、3或4的整数,表示部分Ra的数。在一些实施方案中,x为0、1或2。在一些其他实施方案中,x为0或1。在更进一步的实施方案中,x为0或4。在一些特别实施方案中,x为0。在一些其他特别实施方案中,x为4。
当x不同于0时,每个部分Ra选自C1-C3烷基,例如,选自C1-C2烷基。在一些实施方案中,每个部分Ra是甲基。
部分R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷基-C3-C6环烷基、C1-C6烷氧基-C1-C6烷基、氰基-C1-C6烷基或式(II)的部分
其中环A、R1a和g如本文限定。
在一些实施方案中,R1是C1-C6烷基、C3-C6环烷基、C1-C6烷基-C3-C6环烷基、C1-C6烷氧基-C1-C6烷基、氰基-C1-C6烷基或如本文限定的式(II)的部分。在一些进一步的实施方案中,R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷氧基-C1-C6烷基、氰基-C1-C6烷基或如本文限定的式(II)的部分。在一些进一步的实施方案中,R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷氧基-C1-C6烷基或如本文限定的式(II)的部分。在一些进一步的实施方案中,R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、氰基-C1-C6烷基或如本文限定的式(II)的部分。
在一些实施方案中,R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷基-C3-C6环烷基、氰基-C1-C6烷基或如本文限定的式(II)的部分。在一些进一步的实施方案中,R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷基-C3-C6环烷基或如本文限定的式(II)的部分。
在一些实施方案中,R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷基-C3-C6环烷基、C1-C6烷氧基-C1-C6烷基或氰基-C1-C6烷基。在一些进一步的实施方案中,R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷氧基-C1-C6烷基或氰基-C1-C6烷基。在一些进一步的实施方案中,R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基或氰基-C1-C6烷基。
在一些实施方案中,R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基或C1-C6烷基-C3-C6环烷基。在一些进一步的实施方案中,R1是C1-C6烷基、C3-C6环烷基或C3-C6环烷基-C1-C6烷基。
在一些实施方案中,R1是C1-C6烷基、C3-C6环烷基或如本文限定的式(II)的部分。在一些进一步的实施方案中,R1是C1-C6烷基或C3-C6环烷基,例如R1是C1-C5烷基或C3-C5环烷基;或R1是C1-C3烷基或C3-C4环烷基;或R1是C1-C3烷基或C3环烷基(即环丙基)。
在一些实施方案中,R1是C1-C6烷基或如本文限定的式(II)的部分。在一些进一步的实施方案中,R1是C1-C6烷基。
当R1是C1-C6烷基时,其更特别地可以选自C1-C5烷基或选自C1-C4烷基或选自C1-C3烷基;例如选自甲基和乙基。在一些特别的实施方案中,R1是甲基、乙基或异丙基。在一些其他的特别的实施方案中,R1是甲基。在一些其他的特别的实施方案中,R1是乙基。
当R1是C3-C6环烷基时,其例如可以是C3-C5环烷基或C3-C4环烷基,例如环丙基。
当R1是C3-C6环烷基-C1-C6烷基时,其例如可以是C3-C6环烷基-C1-C3烷基,例如C3-C6环烷基-C1-C2烷基,例如C3-C6环烷基-甲基。在一些实施方案中,当R1是C3-C6环烷基-C1-C6烷基时,其更特别地是C3-C4环烷基-C1-C6烷基或C3-C4环烷基-C1-C3烷基,例如C3-C4环烷基-C1-C2烷基,例如C3-C4环烷基-甲基。在一些实施方案中,当R1是C3-C6环烷基-C1-C6烷基时,C3-C6环烷基更特别地是环丙基。
为避免疑惑,指明当R1是C3-C6环烷基-C1-C6烷基时,R1通过烷基部分连接于式(I)化合物的含氮环。
当R1是C1-C6烷基-C3-C6环烷基时,其例如可以是C1-C3烷基-C3-C6环烷基,例如甲基-C3-C6环烷基。为避免疑惑,指明当R1是C1-C6烷基-C3-C6环烷基时,R1通过环烷基部分连接于式(I)化合物的含氮环。
当R1是C1-C6烷氧基-C1-C6烷基时,其例如可以是C1-C3烷氧基-C1-C6烷基,例如甲氧基-C1-C6烷基。在一些实施方案中,当R1是C1-C6烷氧基-C1-C6烷基时,其更特别地是C1-C6烷氧基-C1-C3烷基,例如C1-C3烷氧基-C1-C3烷基。
当R1是氰基-C1-C6烷基时,其例如可以是氰基-C1-C4烷基或氰基-C1-C3烷基,例如氰基-C1-C2烷基。
在一些实施方案中,R1是式(II)的部分
其中环A、R1a和g如本文限定。
在式(II)的部分中,环A是苯基、5元杂芳基或6元杂芳基。在一些实施方案中,环A是苯基或5元杂芳基。在一些进一步的实施方案中,环A是5或6元杂芳基。在一些实施方案中,环A是苯基。在一些进一步的实施方案中,环A是5元杂芳基。
当环A是5或6元杂芳基时,杂芳基环含有一个或多个优选独立选自N、O和S的杂原子,和至少一个碳原子。在一些实施方案中,杂芳基环含有1-4个杂原子,例如1-3个杂原子或1-2个杂原子或1个杂原子,所述杂原子独立选自N、O和S。在一些实施方案中,当环A是5或6元杂芳基时,其更特别地是5元杂芳基,该杂芳基含有1-4个或1-3个,特别是1或2个选自N、O和S的杂原子。在一些实施方案中,环A是噻吩基。在一些进一步的实施方案中,环A是吡唑基。在一些实施方案中,环A选自苯基、噻吩基和吡唑基,例如苯基、2-噻吩基、3-噻吩基和吡唑-4-基,例如1H-吡唑-4-基。
在式(II)的部分中,g是0至4的整数,表示与环A相连的部分R1a的数。在一些实施方案中,g是0至3的整数。在一些进一步的实施方案中,g是0至2的整数。在另外的进一步的实施方案中,g是1至4的整数。在另外的进一步的实施方案中,g是1至3的整数,例如g是1或2。在一些实施方案中,g是1。
在一些实施方案中,当环A是苯基时,g是1至4或1至3的整数,例如g是1或2,或g是1,当环A是5或6元杂芳基时,g是0至3或0至2的整数,例如g是0或1,例如g是0,或g是1至3的整数,例如g是3。
在一些实施方案中,环A是苯基且g是1至4或1至3的整数,例如g是1或2,或g是1;即式(II)的部分由式(IIa)表示
其中R1a和g如本文限定。
在一些实施方案中,式(IIa)的部分的苯环在对位被取代,即所述部分更具体地如式(IIb)所表示。
其中R1a如本文所定义,且g为1、2或3,例如,g为1或2,或g为1。
因此,在一些实施方案中,本发明的化合物可以由式(Ib)表示
其中每个R1a,R2,每个R3,每个Ra,每个Rb,Z,W,m,n,p,x和y如本文所定义,并且g是1、2或3,例如,g为1或2,或g为1。
在式(Ib)化合物的一些实施方案中,如果g为2,则另外的R1a在苯环(环A)上的间位。在这些实施方案的一些中,在间位的R1a和在对位的R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环。
在式(Ib)化合物的一些实施方案中,其中g为1、2或3,例如,g为1或2,或g为1,并且一个R1a为R1bO,该化合物如式(Ib1)所表示
其中每个R1a,R1b,R2,每个R3,每个Ra,每个Rb,Z,W,m,n,p,x和y如本文所定义,例如,R1b是C1-C3烷基,特别是甲基。
在一些进一步的实施方案中,环A是5或6元杂芳基,特别是5元杂芳基,并且g是0至3的整数。在这些实施方案的一些中,g是0至2的整数,例如0或1,例如g是0。在这些实施方案的一些其他实施方案中,g是1至3的整数,例如g是3。
在式(II)的部分中,任何R1a当存在时独立地选自C1-C6烷基,R1bO和R1cR1dN,并且当g为至少2时,与环A的相邻原子连接的两个R1a可以与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环。
在一些实施方案中,每个R1a独立地选自C1-C6烷基,R1bO和R1cR1dN。在一些实施方案中,每个R1a独立地选自C1-C6烷基和R1bO。在一些实施方案中,每个R1a是R1bO。
在一些实施方案中,每个R1a独立地选自C1-C6烷基和R1bO,并且当g为至少2时,与环A的相邻原子连接的两个R1a可以与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环。
在一些实施方案中,每个R1a是R1bO,并且当g是至少2时,连接到环A的相邻原子的两个R1a可以与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环。
在一些实施方案中,g为至少2,例如g为2,并且与环A的相邻原子连接的两个R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环。
当R1a是C1-C6烷基时,其更特别地可以是C1-C5烷基,或C1-C4烷基,或C1-C3烷基,例如甲基或乙基,特别是甲基。
当与环A的相邻原子连接的两个R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环时,所述环例如可以是非芳族的。在一些实施方案中,所述环是非芳族的并且含有一个或两个杂原子,例如,一个或两个氧原子。在一些实施方案中,当与环A的相邻原子连接的两个R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环时,所述环为5元且非芳族的。在一些实施方案中,所述环是5元非芳族的并且含有一个或两个杂原子,例如,一个或两个氧原子。在一些实施方案中,所述环是非芳族的并且含有一个杂原子,例如一个氧原子,例如所述环是5元的,非芳族的并且含有一个杂原子,例如,一个氧原子。例如,在一些实施方案中,当与环A的相邻原子连接的两个R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环时,所述两个R1a形成下式的二基(diradical)
其中k为1或2;例如k是1。
在一些实施方案中,当与环A的相邻原子连接的两个R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环时,环A为苯基。在这些实施方案的一些中,式(II)部分更具体地是式(IIc)的部分
在任何部分R1bO中,R1b独立地选自H和C1-C6烷基。在一些实施方案中,R1b选自H和C1-C5烷基,或选自H和C1-C4烷基,或选自H和C1-C3烷基,或选自H和C1-C2烷基,或选自H和甲基。在一些实施方案中,R1b选自C1-C6烷基,或选自C1-C5烷基,或选自C1-C4烷基,或选自C1-C3烷基,或选自C1-C2烷基,例如每个R1b是甲基。
在任何部分R1cR1dN中,R1c和R1d独立地选自H和C1-C6烷基。在一些实施方案中,R1c独立地选自H和C1-C5烷基,或选自H和C1-C4烷基,或选自H和C1-C3烷基,或选自H和C1-C2烷基,或选自H和甲基。在一些进一步的实施方案中,R1c选自C1-C6烷基,或选自C1-C5烷基,或选自C1-C4烷基,或选自C1-C3烷基,或选自C1-C2烷基,例如R1c是甲基。同样,R1d独立地选自H和C1-C6烷基。在一些实施方案中,R1d独立地选自H和C1-C5烷基,或选自H和C1-C4烷基,或选自H和C1-C3烷基,或选自H和C1-C2烷基,或选自H和甲基。在一些实施方案中,R1d选自C1-C6烷基,或选自C1-C5烷基,或选自C1-C4烷基,或选自C1-C3烷基,或选自C1-C2烷基,例如R1d是甲基。在一些实施方案中,在任何R1cR1dN中,R1d和R1c两者都是C1-C6烷基,或两者都是C1-C5烷基,或两者都是C1-C4烷基,或两者都是C1-C3烷基,或两者都是C1-C2烷基,例如两者都是甲基。
在一些实施方案中,当环A是5或6元杂芳基时,R1a是C1-C6烷基,例如C1-C3烷基,例如甲基。
在一些特别的实施方案中,R1是甲基、乙基、异丙基、正丙基、环己基、环丙基甲基、甲氧基乙基、氰基甲基、氰基乙基、4-甲氧基苄基、(1,3,5-三甲基-1H-吡唑-4-基)甲基、噻吩-2-基甲基、4-(二甲基氨基)苄基、4-羟基-3-甲氧基苄基、(2,3-二氢苯并呋喃-6-基)甲基或噻吩-3-基甲基。
在式(I)的化合物中,R2是Cl或Br。在一些实施方案中,R2是Cl。在一些其他实施方案中,R2是Br。
在式(I)的化合物中,每个R3独立地选自C1-C6烷基,例如选自C1-C5烷基或选自C1-C4烷基或选自C1-C3烷基;例如R3是甲基或乙基;特别地,R3是甲基。
部分R3的数,由p表示,选自0至3,例如选自0至2,例如p是0或1。在一些实施方案中,p是0。在一些进一步的实施方案中,p是1。例如,在一些实施方案中,当含有Z和W的环是7元的时,p是0,当含有Z和W的环是6元的时,p是0、1或2,例如p是0或1。
在式(I)的化合物中,y是整数0、1、2或3,表示部分Rb的数。在一些实施方案中,y是0、1或2;例如y是0或1。在一些实施方案中,y是0。在一些其他实施方案中,y是1。
部分Rb选自卤素、C1-C3烷基和C1-C3烷氧基,例如选自F、甲基和甲氧基。在一些实施方案中,Rb选自卤素和C1-C3烷氧基,例如选自F和CH3O。在一些实施方案中,Rb是卤素,例如Rb是F。在一些实施方案中,y是1,Rb选自卤素和C1-C3烷氧基,例如选自F和CH3O。在一些实施方案中,当y是1时,Rb是F。在一些进一步的实施方案中,当y是1时,Rb是CH3O。
在一些特别的实施方案中,x和y都是0,即Ra和Rb都不存在。在一些其他的特别的实施方案中,x是0,y是0或1。在一些其他实施方案中,x是0至4的整数,例如x是0或4,y是0或1,例如y是0。
在式(I)的化合物中,Z是N或CH。在一些实施方案中,Z是CH。在一些进一步的实施方案中,Z是N,即式(I)的化合物如式(Ic)表示
其中R1、R2、每个R3、每个Ra、每个Rb、W、m、n、p、x和y如本文限定。
在式(I)的化合物中,W是>Q-R4、-O-或-N(R5)C(O)-。在一些实施方案中,W是>Q-R4或-N(R5)C(O)-。在一些进一步的实施方案中,W是>Q-R4或-O-。在另外的进一步的实施方案中,W是>Q-R4。
在部分>Q-R4中,Q是N或CH。在一些实施方案中,Q是N。在一些实施方案中,因此,W是>N-R4、-O-或-N(R5)C(O)-。
在进一步的实施方案中,W是>N-R4或-N(R5)C(O)-。
在另外的进一步的实施方案中,W是>N-R4或-O-。在另外的进一步的实施方案中,W是>Q-R4,即式(I)的化合物可以由式(Id)表示
其中R1、R2、每个R3、R4、每个Ra、每个Rb、Q、Z、m、n、p、x和y如本文限定。
在式(Id)化合物的一些实施方案中,Q是N,即该化合物可以由式(Id1)表示
其中R1、R2、每个R3、R4、每个Ra、每个Rb、Z、m、n、p、x和y如本文限定。
在式(Id)化合物的一些进一步的实施方案中,Q是CH,即该化合物可以由式(Id2)表示
其中R1、R2、每个R3、R4、每个Ra、每个Rb、Z、m、n、p、x和y如本文限定。
在一些实施方案中,当Q是CH时,Z是N。
在式(Id)化合物的一些实施方案中,
R1是C1-C3烷基;
p是0或1;
R3是C1-C3烷基;
R4是C1-C3烷基、R4a[O(CH2)q]r-Y、R4bS(O)2、R4cC(O)或式(III)的部分
L是直接键或CH2;
h是0至3的整数;
R4a是H或C1-C3烷基;
R4b是C1-C3烷基;
R4c是C1-C3烷基;
R4d是C1-C3烷基;且
环B选自苯基和5或6元杂芳基,优选环B是5或6元杂芳基。
在式(Id)化合物的另外的进一步的实施方案中,
R1是C1-C3烷基;
p是0或1;
R3是C1-C3烷基;
R4是C1-C3烷基、R4a[O(CH2)q]r-Y、R4bS(O)2或R4cC(O);
R4a是H或C1-C3烷基;
R4b是C1-C3烷基;且
R4c是C1-C3烷基。
在另外的进一步的实施方案中,W是-N(R5)C(O)-,即式(I)的化合物可以由式(Ie)表示
其中R1、R2、每个R3、R5、每个Ra、每个Rb、Z、m、n、p、x和y如本文限定。
在式(Ie)的化合物的一些实施方案中,m是2,p是0。在式(Ie)的化合物的一些进一步的实施方案中,m是2,p是0且n是1,即该化合物由式(Ie1)表示
其中R1、R2、R5、每个Ra、每个Rb、Z、x和y如本文限定。
在式(Ie)或(Ie1)化合物的一些实施方案中,Z为N。在一些特别的实施方案中,该化合物如式(Ie2)所表示
其中R1、R2、R5、每个Ra、每个Rb、x和y如本文限定。
在一些其他实施方案中,该化合物如式(Ie3)所表示
其中R1、R2、每个R3、R5、每个Ra、每个Rb、Z、m、n、p、x和y如本文限定。
在式(Ie3)化合物的一些实施方案中,Z是N。在式(Ie3)化合物的一些进一步的实施方案中,Z是N,m是2,p和y都是0。在式(Ie3)化合物的一些进一步的实施方案中,Z是N,m是2,且p、x和y是0。
在式(Ie)、(Ie1)、(Ie2)或(Ie3)的化合物的一些特别的实施方案中,R5是H。
在式(Ie)的化合物一些其他实施方案中,例如式(Ie3)化合物的一些实施方案中,R5是C1-C6烷基、R5a[O(CH2)u]v或式(IV)的部分
其中M、环C、R5b和j如本文限定;例如R5是C1-C6烷基或R5a[O(CH2)u]v;或R5a[O(CH2)u]v,或如本文限定的式(IV)的部分;或R5是R5a[O(CH2)u]v。
含有W和Z的环是6或7元环,即式(I)中的n是0-2的整数,其中当W是>Q-R4或-O-时,n是1或2,并且当W为-N(R5)C(O)-时,n为0或1。
在一些实施方案中,含有W和Z的环是6元的,即当W是>Q-R4或-O-时,式(I)中的n是1;当W是-N(R5)C(O)-时,n是0。在这些实施方案的一些中,Q是N。
在一些实施方案中,含有W和Z的环是6元的,W是>Q-R4或-N(R5)C(O)-,即当W是-N(R5)C(O)-时,n是0,当W是>Q-R4时,n是1。在这些实施方案的一些中,Q是N。
在一些进一步的实施方案中,含有W和Z的环是7元的,即当W是>Q-R4或-O-时,式(I)中的n是2;当W是-N(R5)C(O)-时,n是1。在这些实施方案的一些中,Q是N。
在一些实施方案中,含有W和Z的环是7元的,W是>Q-R4或-N(R5)C(O)-,即当W是-N(R5)C(O)-时,n是1,当W是>Q-R4时,n是2。在这些实施方案的一些中,Q是N。
在一些实施方案中,n是1且W是>Q-R4或-O-。在一些进一步的实施方案中,n是2且W是>Q-R4或-O-。在这些实施方案的一些中,Q是N。
在另外的进一步的实施方案中,W是>Q-R4、-O-或-N(R5)C(O)-,其中当W是>Q-R4时,n是1或2;当W是-O-时,n是1;当W是-N(R5)C(O)-时,n是0或1。在这些实施方案的一些中,Q是N。
在另外的进一步的实施方案中,W是>Q-R4或-O-,当W是>Q-R4时,n是1或2;当W是-O-时,n是1。
在另外的进一步的实施方案中,W是-O-且n是1。
在一些实施方案中,n是1且W是>Q-R4,即该化合物如式(Id)表示,其中n是1。在这些实施方案的一些中,Q是N。
在一些进一步的实施方案中,n是2且W是>Q-R4,即该化合物是式(Id)化合物,其中n是2。在这些实施方案的一些中,Q是N。
在一些实施方案中,W是>Q-R4或-N(R5)C(O)-;且当W是-N(R5)C(O)-时,n是0或1,当W是>Q-R4时,n是1。在这些实施方案的一些中,Q是N。
在一些进一步的实施方案中,W是>Q-R4或-N(R5)C(O)-;当W是-N(R5)C(O)-时,n是0或1,当W是>Q-R4时,n是2。在这些实施方案的一些中,Q是N。
在一些实施方案中,W是>Q-R4或-N(R5)C(O)-;当W是-N(R5)C(O)-时,n是0,当W是>Q-R4时,n是1或2。在这些实施方案的一些中,Q是N。
在一些进一步的实施方案中,W是>Q-R4或-N(R5)C(O)-,当W是-N(R5)C(O)-时,n是1,当W是>Q-R4时,n是1或2。在这些实施方案的一些中,Q是N。
在部分>Q-R4中,R4是C1-C6烷基、R4a[O(CH2)q]r-Y、R4bS(O)2、R4cC(O)、氰基-C1-C6烷基或式(III)的部分
其中L、环B、每个R4d和h如本文限定。
在一些实施方案中,R4是C1-C6烷基、R4a[O(CH2)q]r-Y、R4bS(O)2或如本文限定的式(III)的部分。在一些实施方案中,R4是R4a[O(CH2)q]r-Y、R4bS(O)2、R4cC(O)或如本文限定的式(III)的部分。在一些实施方案中,R4是C1-C6烷基、R4bS(O)2、R4cC(O)或如本文限定的式(III)的部分。在一些实施方案中,R4是C1-C6烷基、R4a[O(CH2)q]r-Y或如本文限定的式(III)的部分。在一些进一步的实施方案中,R4是C1-C6烷基、R4a[O(CH2)q]r-Y、R4cC(O)或如本文限定的式(III)的部分。在一些实施方案中,R4是R4a[O(CH2)q]r-Y、R4cC(O)或如本文限定的式(III)的部分。在一些实施方案中,R4是R4a[O(CH2)q]r-Y、R4bS(O)2或如本文限定的式(III)的部分。在一些实施方案中,R4是R4a[O(CH2)q]r-Y或如本文限定的式(III)的部分。
在一些实施方案中,R4是C1-C6烷基、R4a[O(CH2)q]r-Y、R4bS(O)2或R4cC(O)。在一些实施方案中,R4是C1-C6烷基、R4a[O(CH2)q]r-Y或R4bS(O)2。在一些实施方案中,R4是R4a[O(CH2)q]r-Y、R4bS(O)2或R4cC(O)。在一些实施方案中,R4是C1-C6烷基、R4bS(O)2或R4cC(O)。在一些实施方案中,R4是C1-C6烷基或R4a[O(CH2)q]r-Y。在一些进一步的实施方案中,R4是C1-C6烷基、R4a[O(CH2)q]r-Y或R4cC(O)。在一些实施方案中,R4是R4a[O(CH2)q]r-Y或R4cC(O)。在一些实施方案中,R4是R4a[O(CH2)q]r-Y或R4bS(O)2。
在一些实施方案中,当W是>Q-R4,例如W是>N-R4时,R4是R4a[O(CH2)q]r-Y。
在一些实施方案中,W是>Q-R4,R4是R4a[O(CH2)q]r-Y,即式(I)的化合物可以由式(If)表示
其中R1、R2、每个R3、R4a、每个Ra、每个Rb、Q、Y、Z、m、n、p、q、r、x和y如本文限定。
在式(If)化合物的一些实施方案中,Q是N,即该化合物可以由式(If1)表示
其中R1、R2、每个R3、R4a、每个Ra、每个Rb、Y、Z、m、n、p、q、r、x和y如本文限定。
在式(If)化合物的一些实施方案中,
m是1或2,优选m是2;
R1是C1-C6烷基或式(II)的部分
环A是苯基或5或6元杂芳基;
g是0至3的整数;
每个R1a独立地选自C1-C3烷基、R1bO和R1cR1dN;
每个R1b独立地选自H、C1-C3烷基;
每个R1c独立地选自H和C1-C3烷基;
每个R1d独立地选自H和C1-C3烷基;
或与环A的相邻原子连接的两个R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环;
R2是Cl或Br,优选R2是Br;
p是0或1;
R3是C1-C3烷基;
Z是N或CH;优选Z是N;
n是1或2;
每个q独立地选自2和3;
r是1或2;
Y是直接键或C(O),优选Y是直接键;且
R4a是H或C1-C3烷基。
在式(If),例如式(If1)化合物的一些进一步的实施方案中,
m是1或2,优选m是2;
R1是C1-C6烷基,优选R1是C1-C3烷基;
R2是Cl或Br,优选R2是Br;
p是0或1;
R3是C1-C3烷基;例如R3是甲基;
Z是N或CH;优选Z是N;
n是1或2,优选n是1;
每个q独立地选自2和3;
r是1或2;
Y是直接键或C(O),优选Y是直接键;且
R4a是H或C1-C3烷基。
在式(If),例如式(If1)化合物的一些进一步的实施方案中,m是2;R1是C1-C3烷基;p是0或1;R3是甲基;Z是N;n是1;每个q独立地选自2和3;r是1或2;Y是直接键;且R4a是H或C1-C3烷基。
在一些进一步的实施方案中,当W是>Q-R4,例如W是>N-R4时,R4是式(III)的部分
其中L、环B、h和每个R4d如本文限定。
在一些实施方案中,W是>Q-R4,R4是式(III)的部分,即式(I)的化合物可以由式(Ig)表示
其中R1、R2、每个R3、每个R4d、每个Ra、每个Rb、L、Q、Z、环B、h、m、n、p、r、x和y如本文限定。
在式(Ig)化合物的一些实施方案中,Q是N,即该化合物是式(Ig1)的化合物
其中R1、R2、每个R3、每个R4d、每个Ra、每个Rb、L、Z、环B、h、m、n、p、r、x和y如本文限定。
在式(Ig)化合物的一些特别的实施方案中,R1是C1-C6烷基,特别是C1-C3烷基。在式(Ig)化合物的一些其他特别的实施方案中,n是1。在式(Ig)化合物的另外的进一步的实施方案中,p是0。在式(Ig)化合物的另外的进一步的实施方案中,n是1,p是0。在式(Ig)化合物的一些实施方案中,R1是C1-C6烷基,特别是C1-C3烷基,n是1,p是0。在式(Ig)化合物的一些实施方案中,m是2;例如m是2,n是1,p是0。在式(Ig)化合物的一些实施方案中,m是2,n是1,p是0,R1是C1-C6烷基,特别是C1-C3烷基。在式(Ig)化合物的一些实施方案中,m是1;例如m是1,n是1,p是0。在式(Ig)化合物的一些实施方案中,m是1,n是1,p是0,R1是C1-C6烷基,特别是C1-C3烷基。
在式(Ig)化合物的一些实施方案中,L是亚甲基。在这些实施方案的一些中,环B是5或6元杂芳基,特别是6元杂芳基。在式(Ig)化合物的一些进一步的实施方案中,例如其中环B是5或6元杂芳基,特别是6元杂芳基,L是亚甲基,m是2,n是1,p是0。在一些实施方案中,L是亚甲基,m是2,n是1,p是0,R1是C1-C6烷基,例如C1-C3烷基。在另外的进一步的实施方案中,L是亚甲基,m是1,n是1,p是0,R1是C1-C6烷基,例如C1-C3烷基。
在式(Ig)化合物的一些实施方案中,L是直接键。在这些实施方案的一些中,环B是苯基或6元杂芳基,特别是6元杂芳基。例如,在一些实施方案中,例如其中环B是苯基或6元杂芳基,特别是6元杂芳基,L是直接键,m是2,n是1且p是0。在式(Ig)化合物的一些进一步的实施方案中,例如其中环B是苯基或6元杂芳基,特别是6元杂芳基,L是直接键,m是2,n是1,p是0且R1是C1-C6烷基,例如C1-C3烷基。在另外的进一步的实施方案中,其中环B是苯基或6元杂芳基,环B更特别地是苯基。
当R4是C1-C6烷基时,其更特别地可以是C1-C5烷基或C1-C4烷基或C1-C3烷基或C1-C2烷基,例如CH3。在一些实施方案中,W是>Q-R4,R4是C1-C3烷基,例如甲基或乙基,特别是甲基。
在部分R4a[O(CH2)q]r-Y中,每个q独立地选自1、2、3和4;r是1或2,R4a是H或C1-C6烷基,Y是直接键或C(O)。
在一些实施方案中,Y是直接键,即部分R4a[O(CH2)q]r-Y具有式R4a[O(CH2)q]r-。在一些进一步的实施方案中,Y是C(O),即该部分具有式R4a[O(CH2)q]rC(O)。
在一些实施方案中,r是2,即部分R4a[O(CH2)q]r-Y具有式R4a[O(CH2)q]2-Y。在一些实施方案中,当r是2时,每个q独立地选自2和3。在一些实施方案中,当r是2时,每个q是2,或每个q是3。在一些实施方案中,当r是2时,每个q是2。
在一些进一步的实施方案中,r是1,即该部分是具有式R4aO(CH2)q-Y的部分,其中q是1、2、3或4,例如q是2、3或4,或q是2或3。在一些实施方案中,q是3。在一些实施方案中,r是1,q是1、2或3。在一些进一步的实施方案中,r是1,q是3或4。在一些特别的实施方案中,r是1,q是3。
在一些实施方案中,每个q是2,即该部分是具有式R4a[O(CH2)2]r-Y的部分,其中r是1或2。
在一些实施方案中,q是2且r是1,即该部分具有式R4aO(CH2)-Y。在这些实施方案的一些中,Y是直接键,即该部分具有式R4aO(CH2)2-。在这些实施方案的一些其他实施方案中,Y是C(O),即该部分具有式R4aO(CH2)2C(O)-。
在一些实施方案中,当q是2且r是2时,Y是直接键,即该部分具有式R4aO(CH2)2O(CH2)2-。
在一些实施方案中,每个q是3,即该部分是具有式R4a[O(CH2)3]r-Y的部分,其中r是1或2。在这些实施方案的一些中,Y是直接键。
在一些实施方案中,当q是3时,r是1,即该部分具有式R4aO(CH2)3-Y。在这些实施方案的一些中,Y是直接键,即该部分具有式R4aO(CH2)3-。
在一些进一步的实施方案中,q是3且r是2,即该部分具有式R4a[O(CH2)3]2-Y,即R4aO(CH2)3O(CH2)3-Y。在这些实施方案的一些中,Y是直接键,即该部分具有式R4aO(CH2)3O(CH2)3-。
在一些实施方案中,每个q是4。在一些实施方案中,当q是4时,r是1,即该部分具有式R4aO(CH2)4-Y。在这些实施方案的一些中,Y是直接键,即该部分具有式R4aO(CH2)4-。
在一些实施方案中,每个q是1。在一些实施方案中,当q是1时,r是1,即该部分具有式R4aOCH2-Y。在这些实施方案的一些中,Y是C(O),即该部分具有式R4aOCH2C(O)-。
部分R4a是H或C1-C6烷基。在一些实施方案中,R4a是H或C1-C5烷基,例如R4a是H或C1-C4烷基或R4a是H或C1-C3烷基或R4a是H或C1-C2烷基或R4a是H或甲基。在一些进一步的实施方案中,R4a是C1-C6烷基或R4a是C1-C5烷基,例如R4a是C1-C4烷基或R4a是C1-C3烷基或R4a是C1-C2烷基或R4a是甲基。在一些实施方案中,R4a是H、甲基、乙基或异丙基。在一些实施方案中,R4a是甲基、乙基或异丙基,例如甲基或乙基。在一些实施方案中,R4a是甲基。在一些实施方案中,R4a是乙基。在一些实施方案中,R4a是异丙基。
例如,在一些实施方案中,在式R4a[O(CH2)q]r-Y的部分中,R4a是H、甲基、乙基或异丙基,特别是甲基、乙基或异丙基;q是2、3或4,特别是q是3;r是1;且Y是直接键。
在部分R4bS(O)2中,R4b是C1-C6烷基。在一些实施方案中,R4b是C1-C5烷基;例如R4b是C1-C4烷基;或R4b是C1-C3烷基;或R4b是C1-C2烷基;例如R4b是甲基。
在部分R4cC(O)中,R4c是C1-C6烷基。在一些实施方案中,R4c是C1-C5烷基;例如R4c是C1-C4烷基,例如R4c是甲基或叔丁基;或R4c是C1-C3烷基;或R4c是C1-C2烷基;或R4c是甲基。
在式(III)的部分中
L是直接键,C1-C4亚烷基或-L1-L2-;
L1是直接键或C1-C4亚烷基;
L2是C(O)或NH;
h是0至3的整数,
R4d是C1-C6烷基,且
环B选自苯基和5或6元杂芳基。
在一些实施方案中,L是直接键或C1-C4亚烷基。在一些进一步的实施方案中,L是C1-C4亚烷基或-L1-L2-。在另外的进一步的实施方案中,L是直接键或-L1-L2-。
当L是C1-C4亚烷基时,L更特别地可以是C1-C3亚烷基,或C1-C2亚烷基,或C1亚烷基,即亚甲基。在一些实施方案中,当L是C2-C4亚烷基时,亚烷基部分是支化的,例如其是亚乙基或亚甲基,被1个或2个甲基取代;或亚甲基,被1个或2个甲基取代或被甲基和乙基取代;或亚乙基,被乙基取代。
在一些实施方案中,L是直接键,即式(III)的部分是具有式(IIIa)的部分
其中h、R4d和环B如本文限定。
在一些进一步的实施方案中,L是亚甲基,即式(III)的部分是具有式(IIIb)的部分
其中h、R4d和环B如本文限定。
在部分-L1-L2-中,L1是直接键或C1-C4亚烷基。在一些实施方案中,L1是直接键。在一些其他实施方案中,L1是C1-C4亚烷基。
当L1是C1-C4亚烷基时,其例如可以是C2-C4亚烷基,或C2-C3亚烷基,特别是C2亚烷基,即亚乙基。在一些实施方案中,L2是亚乙基,任选被1或2个甲基取代,或被1个乙基取代。
部分L2是NH或C(O)。在一些实施方案中,L2是NH。在一些进一步的实施方案中,L2是C(O)。
在一些实施方案中,当L是-L1-L2-时,L1是直接键且L2是C(O),或L1是C1-C4亚烷基且L2是NH。
在一些实施方案中,当L是-L1-L2-时,式(III)的部分更特别地具有式(IIIc)
其中L1、L2、环B、R4d和h如本文限定。
在一些实施方案中,L是直接键、CH2、C(O)或-C2-C4亚烷基-NH-;例如直接键、CH2、C(O)或-C2-C3亚烷基-NH-;或直接键、CH2、C(O)或-(CH2)2NH-。
在式(III)的部分中,h是0至3的整数。在一些实施方案中,h是0至2的整数。在一些实施方案中,h是0或1。在一些实施方案中,h是0。在另外的进一步的实施方案中,h是1至3的整数,例如h是1或2,或h是1。
当h是1、2或3时,每个部分R4d独立地选自C1-C6烷基。在一些实施方案中,每个R4d选自C1-C5烷基;例如每个R4d选自C1-C4烷基;或每个R4d选自C1-C3烷基;或每个R4d选自C1-C2烷基;或每个R4d是甲基。应认识到任何R4d可以连接于环B的碳原子或环B的杂原子,例如连接于环B的氮原子。
环B选自苯基和5或6元杂芳基。在一些实施方案中,环B是苯基。在一些实施方案中,环B是5或6元杂芳基。在一些实施方案中,环B是5元杂芳基。在一些实施方案中,环B是6元杂芳基。
当环B是5或6元杂芳基时,所述杂芳基在环内含有一个或多个杂原子,优选选自N、O和S。在一些实施方案中,该杂芳基含有1-4个杂原子,例如1-3个杂原子或1-2个杂原子,所述杂原子选自N、O和S。
在一些实施方案中,当环B是5或6元杂芳基时,所述杂芳基含有一个氮原子(N)和任选至少一个选自N、O和S的另外的杂原子。在一些进一步的实施方案中,当环B是5元杂芳基时,所述环含有一个O或一个S且任选还有一个或多个N。
在一些实施方案中,当环B是5或6元杂芳基时,所述杂芳基可以选自以下环中的任一种
或更特别地选自以下环中的任一种
其中G1是NH、O或S;例如G1是O或S;或G1是O或NH,或G1是NH,且当G1是NH时,NH的氢可以被R4d替代;且G2是N或CH,且当G2是CH时,CH的氢可以被R4d替代。
在一些实施方案中,当环B是6元杂芳基时,其更特别地是选自以下环中的任一种
其中G2是如本文以上限定。在这些实施方案的一些中,G2是CH。在这些实施方案的一些其他实施方案中,G2是N。在一些实施方案中,当环B是6元杂芳基时,其更特别地是
其中G2是如本文以上限定。
在一些进一步的实施方案中,当环B是6元杂芳基时,其更特别地是
其中G2是如本文以上限定。
在一些实施方案中,当环B是5元杂芳基时,其更特别地是选自以下环中的任一种
其中G1和G2如本文以上限定,G1是NH、O或S;例如G1是O或S;或G1是O或NH,或G1是NH,且当G1是NH时,NH的氢可以被R4d替代;且G2是N。在一些进一步的实施方案中,G1是O或S,例如G1是O,且G2是CH或GR4d。
在一些进一步的实施方案中,当环B是5元杂芳基时,其更特别地是
其中G1和G2如本文以上限定。
在一些进一步的实施方案中,当环B是5元杂芳基时,其更特别地是
其中G1和G2如本文以上限定。
在式(I)化合物的一些特别的实施方案中,环B是5或6元杂芳基,如本文以上限定,且R1是C1-C6烷基或C3-C6环烷基,特别是C1-C3烷基或C3环烷基,例如R1是C1-C6烷基或R1是C1-C3烷基。
在一些其他的特别的实施方案中,环B是5或6元杂芳基,如本文以上限定,R1是C1-C6烷基或C3-C6环烷基,特别是C1-C3烷基或C3环烷基,例如R1是C1-C6烷基或R1是C1-C3烷基;且n是1。
在一些其他的特别的实施方案中,环B是6元杂芳基,如本文以上限定,R1是C1-C6烷基或C3-C6环烷基,特别是C1-C3烷基或C3环烷基,例如R1是C1-C6烷基或R1是C1-C3烷基;且n是1。在这些实施方案的一些中,L是直接键。在这些实施方案的一些其他实施方案中,L是亚甲基或C(O),例如L是亚甲基。
在一些其他的特别的实施方案中,环B是5元杂芳基,如本文以上限定,R1是C1-C6烷基或C3-C6环烷基,特别是C1-C3烷基或C3环烷基,例如R1是C1-C6烷基或R1是C1-C3烷基;且n是1。
在一些其他的特别的实施方案中,环B是5元杂芳基,如本文以上限定,R1是C1-C6烷基或C3-C6环烷基,特别是C1-C3烷基或C3环烷基,例如R1是C1-C6烷基或R1是C1-C3烷基;n是1;且L是C1-C4亚烷基或L1-L2,例如L是C1-C4亚烷基或L1-L2,L1是C1-C4亚烷基,且L2是C(O)或NH,特别是NH。
在一些其他的特别的实施方案中,环B是5元杂芳基,如本文以上限定,R1是C1-C6烷基或C3-C6环烷基,特别是C1-C3烷基或C3环烷基,例如R1是C1-C6烷基或R1是C1-C3烷基;n是1;且L是亚甲基。
在式(I)的化合物的一些实施方案中,R4是甲基,乙基,2-羟基乙基,2-甲氧基乙基,2-乙氧基乙基,2-异丙氧基乙基,3-羟基丙基,3-甲氧基丙基,2-(2-甲氧基乙氧基)乙基,4-甲氧基丁基,2-甲氧基乙酰基,3-甲氧基丙酰基,乙酰基,新戊酰基,甲基磺酰基,氰基乙基,3-吡啶基,4-吡啶基,吡嗪-2-基,吡嗪-2-基,苄基,吡啶-2-基甲基,吡啶-3-基甲基吡啶-4-基甲基,(6-甲基吡啶-2-基)甲基,(6-甲基吡啶-3-基)甲基,(5-甲基吡啶-2-基)甲基,嘧啶-5-基甲基,吡嗪-2-基甲基,呋喃-2-基甲基,(5-甲基呋喃-2-基)甲基,呋喃-3-基甲基,1,3-噻唑-2-基甲基,1,3-噻唑-4-基甲基,1,3-噻唑-5-基甲基,(3,5-二甲基异噁唑-4-基)甲基,(1-甲基-1H-咪唑-2-基)甲基,(1H-咪唑-4-基)甲基,或2-((1-甲基-1H-吡唑-5-基)氨基)乙基,吡啶-4-基羰基,吡啶-3-基羰基。
在部分-N(R5)C(O)-中,R5是H、C1-C6烷基、R5a[O(CH2)u]v或式(IV)的部分
其中M、环C、R5b和j如本文限定。
在一些实施方案中,R5是H、C1-C6烷基或R5a[O(CH2)u]v,例如R5是C1-C6烷基或R5a[O(CH2)u]v。在一些实施方案中,R5是H,R5a[O(CH2)u]v,或式(IV)的部分,例如R5是R5a[O(CH2)u]v或式(IV)的部分。在一些实施方案中,R5是C1-C6烷基、R5a[O(CH2)u]v,或式(IV)的部分。在一些实施方案中,R5是H或C1-C6烷基。在一些实施方案中,R5是H或R5a[O(CH2)u]v,例如R5是R5a[O(CH2)u]v。在另外的进一步的实施方案中,R5是H。
当R5是C1-C6烷基时,所述烷基特别地可以是C1-C5烷基或C1-C4烷基或C1-C3烷基或C1-C2烷基,例如甲基。
在一些实施方案中,R5是H或C1-C5烷基,例如R5是H或C1-C4烷基或R5是H或C1-C3烷基或R5是H或C1-C2烷基或R5是H或甲基,或R5是H。
在部分R5a[O(CH2)u]v中,R5a是H或C1-C6烷基,每个u独立地选自1,2,3和4;且v是1或2。在一些实施方案中,每个u是2或3,且v是1或2。在一些实施方案中,每个u是2,即该部分具有式R5a[O(CH2)2]v,其中v是1或2。
在一些实施方案中,其中u是2,v是1,即部分R5a[O(CH2)u]v具有式R5aO(CH2)2。在一些其他实施方案中,其中u是2,v是2,即部分R5a[O(CH2)u]v具有式R5a[O(CH2)2]2,即R5aO(CH2)2O(CH2)2。
在一些实施方案中,每个u是3,即部分R5a[O(CH2)u]v是具有式R5a[O(CH2)3]v的部分,其中v是1或2。在一些实施方案中,其中u是3,v是1,即部分R5a[O(CH2)u]v具有式R5aO(CH2)3。在一些其他实施方案中,其中u是3,v是2,即部分R5a[O(CH2)u]v具有式R5a[O(CH2)3]2,即R5aO(CH2)3O(CH2)3。
在一些实施方案中,v是1,即该部分是具有式R5aO(CH2)u的部分,其中u是1,2,3或4,例如u是2,3或4,特别是u是2或3。
部分R5a是H或C1-C6烷基。在一些实施方案中,R5a是H或C1-C5烷基;例如R5a是H或C1-C4烷基;或R5a是H或C1-C3烷基;或R5a是H或C1-C2烷基;或R5a是H或甲基。在一些进一步的实施方案中,R5a是C1-C6烷基或R5a是C1-C5烷基;例如R5a是C1-C4烷基;或R5a是C1-C3烷基;或R5a是C1-C2烷基;或R5a是甲基。在一些实施方案中,R5a是H,甲基,乙基,或异丙基。在一些实施方案中,R5a是甲基,乙基,或异丙基。在一些实施方案中,R5a是甲基。在一些实施方案中,R5a是乙基。在一些实施方案中,R5a是异丙基。
在一些特别的实施方案中,当R5是R5a[O(CH2)u]v时,u是2或3,v是1,且R5a是H,甲基,乙基,丙基,或异丙基,特别是甲基,乙基,丙基或异丙基,更特别是甲基,乙基,或异丙基。
在一些实施方案中,R5是式(IV)的部分
其中M、环C、R5b和j如本文限定。
在式(IV)的部分中,M是直接键或C1-C4亚烷基;环C选自苯基和5或6元杂芳基,例如环C是苯基;R5b是C1-C6烷基,例如R5b是C1-C3烷基或R5b是甲基;且j是0至3的整数,例如j是0,1或2,或j是0或1,或j是0。在一些实施方案中,式(IV)的部分是苄基。
应该认识到,本发明的化合物可以同时属于上文提到的多于一个不同的实施方案,并且因此可以同时由多于一个的上式表示,除非另有说明或从上下文中显而易见,或除非所述实施方案或式是相互排斥的。因此,在一些实施方案中,式(Ia)化合物也是式(Ic)化合物,即由式(Ih)表示的化合物
其中R1,R2,每个R3,每个Ra,每个Rb,W,n,p,x,和y如本文限定。
同样,在一些实施方案中,式(Ia)化合物也是式(Id)化合物,即由式(Ij)表示的化合物
其中R1,R2,每个R3,R4,每个Ra,每个Rb,Q,Z,n,p,x,和y如本文限定。
在另外的进一步的实施方案中,式(Ij)的化合物也是式(Ic)的化合物,即由式(Ik)表示的化合物
其中R1,R2,每个R3,R4,每个Ra,每个Rb,Q,n,p,x,和y如本文限定。
在进一步的实施方案中,式(Ia)的化合物也是式(If)的化合物,即由式(Im)表示的化合物
其中R1,R2,每个R3,R4a,每个Ra,每个Rb,Q,Y,Z,n,p q,r,z和y如本文限定。
在进一步的实施方案中,式(Im)的化合物也是式(Ic)的化合物,即由式(In)表示的化合物
其中R1,R2,每个R3,R4a,每个Ra,每个Rb,Q,Y,n,p q,r,z和y如本文限定。
在式(In)的化合物的一些实施方案中,Q是N,即该化合物由式(In1)表示
其中R1,R2,每个R3,R4a,每个Ra,每个Rb,Y,n,p q,r,z和y如本文限定。
在一些进一步的实施方案中,式(Ic)的化合物也是式(Id)化合物,即由式(Io)表示的化合物
其中R1,R2,每个R3,R4,每个Ra,每个Rb,Q,m,n,p,x和y如本文限定。
在另外的进一步的实施方案中,式(Io)的化合物也是式(If)的化合物,即由式(Ip)表示的化合物
其中R1,R2,每个R3,R4a,每个Ra,每个Rb,Q,m,n,p,q,r,x和y如本文限定。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,x是0且y是0或1;或x和y都是0。
在式(If)、(Im)、(In)或(Ip)的化合物的一些进一步的实施方案中,
x是0且y是0或1,或x和y都是0;且
R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷基-C3-C6环烷基、C1-C6烷氧基-C1-C6烷基或氰基-C1-C6烷基;特别地R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷氧基-C1-C6烷基或氰基-C1-C6烷基;或R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基;例如R1是C1-C6烷基。
在式(If)、(Im)、(In)或(Ip)的化合物的一些进一步的实施方案中,
x是0;y是0或1;且
R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷基-C3-C6环烷基、C1-C6烷氧基-C1-C6烷基或氰基-C1-C6烷基;特别地R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷氧基-C1-C6烷基或氰基-C1-C6烷基;或R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基;例如R1是C1-C6烷基。
在一些实施方案中,式(I)的化合物更特别地由式(If)表示,或由式(Im)表示或由式(In)表示,或由式(Ip)表示,其中
R1是C1-C6烷基、C3-C6环烷基、C3-C6环烷基-C1-C6烷基、C1-C6烷基-C3-C6环烷基、C1-C6烷氧基-C1-C6烷基、氰基-C1-C6烷基;例如R1是C1-C6烷基、C3-C6环烷基或C3-C6环烷基-C1-C6烷基;或R1是C1-C6烷基或C3-C6环烷基,特别是R1为C1-C6烷基;
p是0至3的整数;例如p是0-2,或p是0或1;特别地p是0;
当p不是0时,每个R3独立地选自C1-C6烷基;例如各自是甲基;
n是1或2,例如n是1;
每个q独立地选自2和3,例如每个q是2,或每个q是3;
r是1或2,例如r是1;且
R4a是H或C1-C6烷基,例如R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基。
在一些实施方案中,式(I)的化合物更特别地由式(If)表示,或由式(Im)表示或由式(In)表示,或由式(Ip)表示,其中
q是2,3或4,例如q是2或3,特别是q是3;
r是1;且
R4a是H或C1-C6烷基,例如R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,Y是直接键。在式(If)、(Im)、(In)或(Ip)的化合物的一些进一步的实施方案中,Y是C(O)。
例如,在一些实施方案中,式(I)的化合物更特别地由式(If)表示,或由式(Im)表示或由式(In)表示,或由式(Ip)表示,其中q是2,3或4,例如q是2或3,特别是q是3;r是1;Y是直接键;且R4a是H或C1-C6烷基,例如R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是C1-C3烷基或C3环烷基,特别是C1-C3烷基;p是0或1,特别是p是0;R3是C1-C3烷基,例如甲基;n是1或2,例如n是1;每个q独立地选自2和3;例如每个q是2;r是1或2,例如r是1;且R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是C1-C3烷基;n是1;p是0;q是2;r是1;且R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是甲基或乙基;n是1;p是0;q是2;r是1;且R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是如本文限定;p是0或1,特别是p是0;R3是C1-C3烷基,例如甲基;n是1或2,例如n是1;每个q是2;r是2;且R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是如本文限定,例如R1是C1-C6烷基或C1-C3烷基;p是0或1,特别是p是0;R3是C1-C3烷基,例如甲基;n是1或2,例如n是1;q是3;r是1;且R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是C1-C6烷基,例如C1-C3烷基;p是0或1,特别是p是0;R3是C1-C3烷基,例如甲基;n是1;q是3;r是1;且R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是C1-C3烷基;R2是Br;R3是C1-C3烷基,更优选R3是甲基;Y是直接键;且p是0或1,优选p是0。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,m是2;R1是C1-C3烷基;R2是Br;R3是C1-C3烷基,优选R3是甲基;Y是直接键;n是1;p是0或1;q是2;且r是1。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,m是2;R1是C1-C3烷基;R2是Br;R3是C1-C3烷基,优选R3是甲基;Y是直接键;n是1;p是0或1;优选p是0;q是3;且r是1。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是C1-C6烷基,优选R1是C1-C3烷基;R2是Cl或Br,优选R2是Br;R3是C1-C3烷基,优选R3是甲基;Y是直接键;n是1或2,优选n是1;p是0或1,优选p是0;每个q独立地选自2和3,优选每个q是2;且r是1或2,优选r是1。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是C1-C6烷基,优选R1是C1-C3烷基;R2是Cl或Br,优选R2是Br;Y是直接键;n是1或2,优选n是1;p是0;q是3;且r是1。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是C1-C3烷基;R3是甲基;R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基;Y是直接键;n是1;p是0或1;q是2;且r是1。
在式(If)、(Im)、(In)或(Ip)的化合物的一些实施方案中,R1是C1-C3烷基;R4a是H或C1-C3烷基,特别是R4a是H,甲基,乙基,或异丙基;Y是直接键;n是1;p是0;q是3;且r是1。
在一些实施方案中,该化合物由式(Iq)表示,
其中环A,每个R1a,R2,每个R3,每个Ra,每个Rb,Z,W,g,m,n,p,x和y如本文限定。
在式(Iq)的化合物的一些实施方案中,当W是>Q-R4,例如W是>N-R4时,R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,或R4cC(O)。例如,在式(Iq)的化合物的一些实施方案中,W是>Q-R4,或W是-N(R5)C(O)-,例如W是>N-R4或-N(R5)C(O)-,且当W是>Q-R4或>N-R4时,R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,或R4cC(O)。
在式(Iq)的化合物的一些实施方案中,W是>Q-R4,且R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,或R4cC(O)。在一些实施方案中,W是>N-R4,且R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,或R4cC(O)。
在式(Iq)的化合物的一些进一步的实施方案中,该化合物也是由式(If)表示的化合物,或由式(Im)表示或由式(In)表示,或由式(Ip)表示。
在一些实施方案中,该化合物由式(Ir)表示,
其中R1,R2,每个R3,每个Ra,每个Rb,Z,W,n,p,和y如本文限定,x1和x2中的每个是独立选自0,1和2的整数,x1和x2一起表示部分Ra的总数。在一些实施方案中,x1和x2都是0。在一些进一步的实施方案中,x1和x2独立选自1和2,例如都是2。在一些实施方案中,x1和x2都是0,或x1和x2都是2;例如x1和x2都是0,或x1和x2都是2且每个Ra是甲基。在一些实施方案中,当x1和x2中的一者或二者不同于0时,R1是C1-C6烷基或C3-C6环烷基-C1-C6烷基,例如R1是C1-C6烷基,例如C1-C3烷基。
在式(Ir)的化合物的一些实施方案中,x是0至4的整数,例如x是0或4,且y是0或1,例如y是0。
在一些实施方案中,每个Ra是甲基且x1和x2都是2,即该化合物由式(Ir1)表示
其中R1,R2,每个R3,每个Rb,Z,W,n,p,和y如本文限定。
在一些实施方案中,式(Ir)的化合物也是式(Ic),(Id),(Id1),(Id2),(Ie),(If),(If1),(Ig),(Ig1),(Io),或(Ip)任一种的化合物。
在式(I)化合物的一些进一步的实施方案中,
m是1或2,优选m是2;
R1是C1-C6烷基,或式(II)的部分
环A是苯基或5或6元杂芳基;
g是0至3的整数;
每个R1a独立地选自C1-C3烷基、R1bO和R1cR1dN;
每个R1b独立地选自H,C1-C3烷基;
每个R1c独立地选自H和C1-C3烷基;
每个R1d独立地选自H和C1-C3烷基;
或与环A的相邻原子连接的两个R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环;
R2是Cl或Br;
p是0或1;
R3是C1-C3烷基;
Z是N或CH;优选Z是N;
W是>N-R4,-O-,或-N(R5)C(O)-;优选W是>N-R4,或-N(R5)C(O)-;
当W是>N-R4或-O-时,n是1或2;
当W是-N(R5)C(O)-时,n是0或1;
R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,R4cC(O)或式(III)的部分
每个q独立地选自2和3;
r是1或2;
h是0至3的整数;
L是直接键或亚甲基;
Y是直接键或C(O),优选Y是直接键;
R4a是H或C1-C3烷基;
R4b是C1-C3烷基;
R4c是C1-C3烷基;
R4d是C1-C3烷基;
R5是H或C1-C3烷基;且
环B选自苯基和5或6元杂芳基,优选环B是5或6元杂芳基。
在式(I)的化合物另外的进一步的实施方案中,
m是1或2;
R1是C1-C3烷基;
R2是Cl或Br;
p是0或1;
R3是C1-C3烷基;
Z是N或CH;优选Z是N;
W是>N-R4,-O-或-N(R5)C(O)-,优选W是>N-R4,或-N(R5)C(O)-;
当W是>N-R4或-O-时,n是1或2;
当W是-N(R5)C(O)-时,n是0或1;
R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,R4cC(O)或式(III)的部分
每个q独立地选自2和3;
r是1或2;
h是0至3的整数;
L是直接键或亚甲基;
Y是直接键或C(O),优选Y是直接键;
R4a是H或C1-C3烷基;
R4b是C1-C3烷基;
R4c是C1-C3烷基;
R4d是C1-C3烷基;
R5是H或C1-C3烷基;且
环B选自苯基和5或6元杂芳基,优选环B是5或6元杂芳基。
在式(I)的化合物另外的进一步的实施方案中,
m是1或2,优选m是2;
R1是C1-C3烷基;
R2是Cl或Br;
p是0或1;
R3是C1-C3烷基;
Z是N或CH;优选Z是N;
W是>N-R4,或-N(R5)C(O)-;
当W是>N-R4时,n是1或2;
当W是-N(R5)C(O)-时,n是0或1;
R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,R4cC(O)或式(III)的部分
每个q独立地选自2和3;
r是1或2;
L是直接键或亚甲基;
h是0至3的整数;
Y是直接键或C(O),优选Y是直接键;
R4a是H或C1-C3烷基;
R4b是C1-C3烷基;
R4c是C1-C3烷基;
R4d是C1-C3烷基;
R5是H或C1-C3烷基;且
环B选自苯基和5或6元杂芳基,优选环B是5或6元杂芳基。
在以上一些实施方案中,x是0,且y是0或1。在以上其他一些实施方案中,x和y都是0。
在式(I)的化合物一些进一步的实施方案中,
x是0;
m是1或2;
R1是C1-C6烷基,C3-C6环烷基,或式(II)的部分
环A是苯基或5或6元杂芳基;
g是0至3的整数;
每个R1a独立地选自C1-C6烷基,R1bO,和R1cR1dN;
每个R1b独立地选自H和C1-C6烷基;
每个R1c独立地选自H和C1-C6烷基;
每个R1d独立地选自H和C1-C6烷基;
或与环A的相邻原子连接的两个R1a与它们所连接的原子一起形成任选含有一个或多个杂原子的5或6元环;
R2是Cl或Br;
p是0至3的整数;
每个R3独立地选自C1-C6烷基;
y是0;
Z是N或CH;
W是>N-R4,-O-或-N(R5)C(O)-;
当W是>N-R4或-O-时,n是1或2;
当W是-N(R5)C(O)-时,n是0或1;
R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,R4cC(O),或式(III)的部分
每个q独立地选自2和3;
r是1或2;
h是0至3的整数;
Y是直接键或C(O);
L是直接键或亚甲基;
R4a是H或C1-C6烷基;
R4b是C1-C6烷基;
R4c是C1-C6烷基;
R4d是C1-C6烷基;
环B选自苯基和5或6元杂芳基;
R5是H,C1-C6烷基或R5a[O(CH2)u]v;
R5a是H或C1-C6烷基;
u是2或3;且
v是1或2。
如本文以上所述,在一些实施方案中,x是0。在这样的实施方案中,该化合物可以由式(Is)表示
其中R1,R2,每个R3,每个Rb,Z,W,m,n,p,和y如本文限定。
在式(I),例如式(Ir)、(Ir1)或(Is)的化合物的一些实施方案中,y是0或1,例如y是0。因此,例如,在一些实施方案中,该化合物可以由式(Is1)表示
其中R1,R2,每个R3,每个Rb,Z,W,m,n,和p如本文限定。
在一些进一步的实施方案中,该化合物由式(It)表示
其中R1,R2,每个R3,每个Ra,每个Rb,Z,W,m,n,p,和x如本文限定,y1是0或1,且y2是0,1,或2;例如y2是0或1,或y2是0。
在式(It)的化合物的一些实施方案中,y2是0,即该化合物由式(It1)表示
其中R1,R2,每个R3,每个Ra,Rb,Z,W,m,n,p,x,和y1如本文限定。在式(It1)的化合物的一些实施方案中,y1是1。
在一些实施方案中,式(It)的化合物也是式(Ir)的化合物,即由式(Iu)表示的化合物
其中R1,R2,每个R3,每个Ra,每个Rb,Z,W,n,p,x1,x2,y1和y2如本文限定。在式(Iu)化合物的一些实施方案中,y1和y2都是0,或y1和y2之一是0,例如y2是0。在式(Iu)的化合物的一些进一步的实施方案中,x1和x2都是0,y1是0或1,且y2是0。在式(Iu)的化合物的另外的进一步的实施方案中,x1和x2都是0或都是2。
在一些进一步的实施方案中,该化合物由式(Iv)表示
其中R1,R2,每个R3,每个Ra,每个Rb,Z,W,m,n,p,和x如本文限定,y1是0或1,且y2是0,1,或2;例如y2是0或1,或y2是0。
在式(Iv)化合物的一些实施方案中,y2是0,即该化合物由式(Iv1)表示
其中R1,R2,每个R3,每个Ra,Rb,Z,W,m,n,p,x,和y1如本文限定。在式(Iv1)化合物的一些实施方案中,y1是1。
在一些实施方案中,式(Iv)的化合物也是式(Ir)的化合物,即由式(Ix)表示的化合物
其中R1,R2,每个R3,每个Ra,每个Rb,Z,W,n,p,x1,x2,y1和y2如本文限定。在式(Ix)化合物的一些实施方案中,y1和y2都是0,或y1和y2之一是0,例如y2是0。在式(Ix)化合物的一些进一步的实施方案中,x1和x2都是0,y1是0或1,且y2是0。在式(Iv)化合物的另外的进一步的实施方案中,x1和x2都是0,或x1和x2都是2。
在式(I)化合物的一些进一步的实施方案中,例如式(Ia),(Ib),(Ic),(Ih),(Iq),(Ir),(Ir1),(Is),(Is1),(It),(It1),(Iu),(Iv),(Iv1),或(Ix)的化合物的一些实施方案中,W是>Q-R4,或-N(R5)C(O)-;R4是R4a[O(CH2)q]r-;且R5是R5a[O(CH2)u]v-。
在式(I)化合物的一些特别的实施方案中,
x是0至4的整数;例如x是0;
每个Ra是甲基;
m是1或2;
R1是甲基,乙基,异丙基,正丙基,环己基,环丙基甲基,甲氧基乙基,氰基甲基,氰基乙基,4-甲氧基苄基,(1,3,5-三甲基-1H-吡唑-4-基)甲基,噻吩-2-基甲基,4-(二甲基氨基)苄基,4-羟基-3-甲氧基苄基,(2,3-二氢苯并呋喃-6-基)甲基,噻吩-3-基甲基;
R2是Cl或Br;
p是0或1;
R3是甲基;
y是0或1;例如y是0;
Rb选自F和甲氧基;
Z是N或CH;
W是>Q-R4,-O-或-N(R5)C(O)-;
Q是N或CH;
当W是>N-R4或-O-时,n是1或2;
当W是-N(R5)C(O)-时,n是0或1;
R4是甲基,乙基,2-羟基乙基,2-甲氧基乙基,2-乙氧基乙基,2-异丙氧基乙基,3-羟基丙基,3-甲氧基丙基,2-(2-甲氧基乙氧基)乙基,4-甲氧基丁基,2-甲氧基乙酰基,3-甲氧基丙酰基,乙酰基,新戊酰基,甲基磺酰基,氰基乙基,3-吡啶基,4-吡啶基,吡嗪-2-基,吡嗪-2-基,苄基,吡啶-2-基甲基,吡啶-3-基甲基吡啶-4-基甲基,(6-甲基吡啶-2-基)甲基,(6-甲基吡啶-3-基)甲基,(5-甲基吡啶-2-基)甲基,嘧啶-5-基甲基,吡嗪-2-基甲基,呋喃-2-基甲基,(5-甲基呋喃-2-基)甲基,呋喃-3-基甲基,1,3-噻唑-2-基甲基,1,3-噻唑-4-基甲基,1,3-噻唑-5-基甲基,(3,5-二甲基异噁唑-4-基)甲基,1(1-甲基-1H-咪唑-2-基)甲基,(1H-咪唑-4-基)甲基,2-((1-甲基-1H-吡唑-5-基)氨基)乙基,吡啶-4-基羰基,或吡啶-3-基羰基;且
R5是H,甲基,2-甲氧基乙基,3-甲氧基丙基,2-乙氧基乙基,2-异丙氧基乙基,或苄基。
如本文以上所述,在式(I)的化合物中,含有Z和W的环可以在对位或间位连接于苯环,分别对应于式(I′)和(I″)的化合物。应该认识到,这也适用于所有上述实施方案。因此,在一些实施方案中,根据任何上式(Ia)至(Ix)的化合物中,含有Z和W的环在对位连接于苯环。在一些进一步的实施方案中,根据任何上式(Ia)至(Ix)的化合物中,含有Z和W的环在间位连接于苯环。
还应该认识到,本文对式(I)化合物的任何提及也暗示指根据其任何实施方案的化合物,例如,如上述式(Ia)至(Ix)中任一种所示,除非另有说明或从上下文中显而易见。
本发明包括药物组合物,所述药物组合物包含至少一种根据式(I)的化合物或其单独的异构体、异构体的外消旋或非外消旋混合物或药学上可接受的盐和至少一种药学上可接受的赋形剂,例如载体,以及任选的其他治疗和/或预防成分。
根据本发明的药物组合物可用于局部(局部的)或全身给药,例如,用于肠内给药,例如直肠或口服给药,或用于肠胃外给药至哺乳动物(特别是人),并且包括治疗有效量的根据本发明的化合物或其药学上可接受的盐作为活性成分,连同药学上可接受的赋形剂,例如药学上可接受的载体。活性成分的治疗有效量如上文所定义并且取决于例如哺乳动物的种类、体重、年龄、个体状况、个体药代动力学数据、待治疗的疾病和给药方式。对于肠内给药,例如口服给药,本发明化合物可以配制成广泛的多种剂型。
所述药物组合物和剂型可以包含一种或多种本发明的化合物或其一种或多种药学上可接受的盐作为活性组分。药学上可接受的载体可以是固体或液体。固体形式的制剂包括粉剂、片剂、丸剂、锭剂、胶囊剂、扁囊剂、栓剂和可分散的颗粒剂。固体载体可以是还可用作稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或包封材料的一种或多种物质。在粉剂中,载体通常是细碎的固体,其是与细碎的活性组分的混合物。在片剂中,活性组分通常与具有必要粘合能力的载体以合适的比例混合并按所需的形状和尺寸压实。合适的载体包括但不限于碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。活性化合物的制剂可以包括作为载体的包封材料,提供胶囊,其中有或没有载体的活性组分被与其结合的载体包围。
适于口服给药的其他形式包括液体形式制剂,包括乳液、糖浆剂、酏剂、水溶液、水性混悬液或意图在使用前不久转化成液体形式制剂的固体形式制剂。乳液可以在溶液中制备,例如在丙二醇水溶液中,或者可以含有乳化剂,例如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶。水溶液可以通过将活性组分溶解在水中并加入合适的着色剂、香料、稳定剂和增稠剂来制备。水性混悬液可以通过将细碎的活性组分用粘性材料如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素钠和其他众所周知的悬浮剂分散在水中制备。固体形式的制剂包括溶液剂、混悬剂和乳液,除了活性组分外,还可以含有着色剂、香料、稳定剂、缓冲剂、人造和天然甜味剂、分散剂、增稠剂、增溶剂等。
用于直肠给药的示例性组合物包括栓剂,其可以包含例如合适的非刺激性赋形剂,例如可可脂、合成甘油酯或聚乙二醇,其在常温下是固体,但是在直肠腔中液化和/或溶解以释放药物。
本发明的化合物也可以肠胃外给药,例如,通过吸入、注射或输注,例如通过静脉内、动脉内、骨内、肌内、大脑内、脑室内、滑膜内、胸骨内、鞘内、病灶内、颅内、肿瘤内、皮内和皮下注射或输注。
因此,对于肠胃外给药,本发明的药物组合物可以是无菌可注射或可输注制剂的形式,例如,作为无菌水性或油性混悬液。该混悬液可以根据本领域已知的技术使用合适的分散剂或润湿剂(例如吐温80)和悬浮剂来配制。无菌可注射或可输注制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射或可输注溶液或混悬液。例如,药物组合物可以是1,3-丁二醇中的溶液。可用于本发明组合物中的可接受的媒介和溶剂的其他实例包括但不限于甘露醇、水、林格(Ringer's)溶液和等渗氯化钠溶液。此外,无菌非挥发性油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的非挥发性油,包括合成的甘油单酯或甘油二酯。脂肪酸如油酸及其甘油酯衍生物可用于制备注射剂,同样还有天然的药学上可接受的油,例如橄榄油或蓖麻油,特别是其聚氧乙基化形式。这些油溶液或混悬液也可含有长链醇稀释剂或分散剂。用于肠胃外使用的溶液也可以包含合适的稳定剂,如果需要,也可以包含缓冲物质。合适的稳定剂包括抗氧化剂,例如单独或组合的硫酸氢钠、亚硫酸钠或抗坏血酸、柠檬酸及其盐和EDTA钠。肠胃外溶液也可以包含防腐剂,如苯扎氯铵、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯和氯丁醇。
对于吸入或鼻腔给药,合适的药物制剂是颗粒、气溶胶、粉末、雾或小滴,例如平均尺寸为直径约10μm或更小。例如,可以在盐水中制备溶液形式的用于吸入的组合物,使用苄醇或其他合适的防腐剂,用于提高生物利用度的吸收促进剂,氟碳和/或本领域已知的其他增溶剂或分散剂。
本发明的药物组合物也可以局部给药至皮肤或粘膜。对于局部应用,药物组合物可以是例如为洗剂、凝胶、糊剂、酊剂、透皮贴剂、用于经粘膜递送的凝胶。
所述组合物可以用包含悬浮或溶解在载体中的活性组分的合适的软膏配制。用于局部给予本发明化合物的载体包括但不限于矿物油、液体石油、白色石油、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者,药物组合物可以配制成包含悬浮或溶解在载体中的活性化合物的合适的洗剂或霜剂(cream)。合适的载体包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、鲸蜡基酯蜡、鲸蜡醇、2-辛基十二烷醇、苄醇和水。本发明的药物组合物也可以通过直肠栓剂制剂或在合适的灌肠制剂中局部施用于下肠道。合适的药物赋形剂(例如载体)和制备药物剂型的方法描述于药物制剂领域的标准参考教科书Remington's Pharmaceutical Sciences,Mack Publishing Company中。
药物组合物可以包含约1%至约95%,优选约20%至约90%的式(I)化合物,以及至少一种药学上可接受的赋形剂。
通常,本发明的化合物将以治疗有效量通过用于起类似效用的药剂的任何接受的给药方式给予。合适的日剂量通常为1至1000mg,例如每天1-500mg,或每天1-50mg,取决于许多因素,例如待治疗的疾病的严重程度、患者的年龄和相对健康状况、使用的化合物的效力、给药途径和形式以及给药所针对的适应症等。治疗这些疾病的技术领域的普通技术人员将能够在没有过度实验,依赖个人知识和本申请的公开的情况下,确定对于给定疾病本发明化合物的治疗有效量。本发明的化合物可以作为药物制剂给予,包括适合于肠内或肠胃外给药的制剂。
优选的给药方式一般是口服,使用方便的日剂量方案,其可根据患病程度进行调整。
如本文所定义的式(I)化合物或其药学上可接受的盐可用于治疗其中调节哺乳动物(例如人)的酪氨酸激酶ROR1活性是有益的病症或失调,例如恶性过度增殖性失调、肥胖相关的代谢并发症、自身免疫失调或炎性病症,以及用于制造治疗这种失调或病症的药物的方法。
在一些实施方案中,式(I)化合物或其药学上可接受的盐可用于治疗恶性过度增殖性失调,或用于制造治疗这种失调或病症的药物的方法。
在一些实施方案中,如本文所定义的式(I)化合物或其药学上可接受的盐可用于治疗肥胖相关的代谢并发症,以及用于制造治疗这种失调或病症的药物的方法。
在一些实施方案中,如本文所定义的式(I)化合物或其药学上可接受的盐可用于治疗自身免疫失调,以及用于制造治疗这种失调或病症的药物的方法。
在一些实施方案中,如本文所定义的式(I)化合物或其药学上可接受的盐可用于治疗炎性失调,以及用于制造治疗这种失调或病症的药物的方法。
式(I)化合物可由本领域普通技术人员使用常规化学合成方法制备。
根据本发明的中间体和化合物的制备可以特别通过以下方案1-5说明。
方案1
式(I)化合物可以例如根据方案1中所示的路线制备。在氧化剂如硝基苯存在下,在150-160℃下,2,3-二氨基吡啶101与醛102缩合,导致形成式(I)的咪唑并吡啶(Yadagiri,B and Lown,W J,Synth.Communications,1990,20(7),955-963)。
或者,101和102可以在空气和对甲苯磺酸存在下在DMF中在80℃下转化为式(I)化合物(Xiangming,H,et al.,ARKIVOC,2007,xiii,150-154)。
方案2
或者,可以通过方案2中所示的顺序实现式(I)化合物的合成。在合适的偶联剂如1-丙烷膦酸环酐或TBTU存在下,用合适的羧酸103处理2,3-二氨基吡啶101,得到中间体酰胺104,然后在140℃至160℃之间在乙酸中加热,产生式(I)化合物。
方案3
必要的2,3-二氨基吡啶101可以通过方案3中概述的顺序制备。用适当的胺106在异丙醇中在升高的温度下处理4-氯-3-硝基-2-氨基吡啶105,通过芳族亲核取代产生中间体107。然后在酸性条件下通过合适的还原剂如铁金属、锌金属或SnCl2将中间体107容易地还原成所需的2,3-二氨基吡啶101。
或者,可以从中间体107开始,在方案4中所示的一锅反应中进行还原和环化步骤,一步制备式(I)化合物。然后用连二亚硫酸钠在乙醇和水中在60-70℃下完成由107和醛102形成式(I)化合物。(Yang,D,et al.,Synthesis,2005,47-56)。
方案4
方案5中显示了制备式(I)化合物的另一种方法。该方法包括在n-BuOH中在120-160℃下通过咪唑并[4,5-b]吡啶中间体108中的氯的芳族亲核取代在最后一步中引入胺106。(Wang,T,et al.,Bioorg.Med.Chem.Lett.,2012,2063-2069)。中间体108可以通过方案1中所示的方法制备。
方案5
用于制备式(I)化合物的必要起始原料可商购获得,或者可通过本领域已知的方法制备。
可以进行下面实验部分中描述的反应,得到游离碱形式或作为酸加成盐的本发明化合物。术语化合物的药学上可接受的盐是指如本文所定义的药学上可接受的盐,并且具有母体化合物的所需药理学活性。可以根据从游离碱制备酸加成盐的常规程序,通过将游离碱溶解在合适的有机溶剂中并用酸处理该溶液来获得药学上可接受的酸加成盐。
加成盐的实例包括与无机酸形成的盐或与有机酸形成的盐,所述无机酸例如,盐酸、氢溴酸、硫酸、硝酸、磷酸;所述有机酸例如,乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、葡萄糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、酒石酸、对甲苯磺酸或三甲基乙酸。
式(I)化合物可具有一个或多个手性碳原子,因此可以以光学异构体的形式获得,例如,作为纯对映体,或作为对映体的混合物(外消旋体)或作为非对映体的混合物获得。分离光学异构体混合物以获得纯对映体是本领域公知的,并且可以例如通过用光学活性(手性)酸分级结晶盐或通过在手性柱上进行色谱分离来实现。
本文所述的合成路线中使用的化学品可包括例如溶剂、试剂、催化剂和保护基团和脱保护基团试剂。保护基团的实例是叔丁氧基羰基(Boc)、苄基、三苯甲基(三苯基甲基)和三甲基甲硅烷基。上述方法还可另外包括在本文具体描述的步骤之前或之后的步骤,以添加或除去合适的保护基团,以最终使得合成化合物。另外,各种合成步骤可以以交替的次序或顺序进行,以得到所需的化合物。合成化学转化和保护基团方法是本领域已知的,包括例如R.C.Larock,Comprehensive Organic Transformations,VCH Publishers(1989);L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,JohnWiley and Sons(1994);L.A.Paquette,ed.,Encyclopedia of Reagents for OrganicSynthesis,John Wiley and Sons(1995);T.H.Greene and P.G.M.Wuts,ProtectiveGroups in Organic Synthesis,3rd Ed.,John Wiley and Sons(1999);以及P.J.Kocieński,Protecting Groups,Georg Thieme Verlag,(2000),及其随后的版本中描述的那些。
以下缩写用于此处:
Boc 叔丁氧基羰基
DCE 1,2-二氯乙烷
DCM 二氯甲烷
DIPEA N,N-二异丙基乙基胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
ESI 电喷雾离子化
EtOAc 乙酸乙酯
EtOH 乙醇
HPLC 高效液相色谱
i-PrOH 异丙醇
MeOH 甲醇
MS 质谱
NBS N-溴琥珀酰亚胺
NCS N-氯琥珀酰亚胺
NMR 核磁共振
实施例和中间体化合物
实验方法
在配备有三重共振冷探头(triple resonance cold probe)的Varian Inova 600上记录1H NMR和13C NMR波谱。使用残余溶剂质子共振作为内标记录所有波谱。分析型HPLC在Agilent Series 1100系统上进行,使用ACE C8(3μm,3.0x50mm)柱,以0.1%甲酸/MilliQH2O/CH3CN为流动相(酸性系统),或使用Gemini NX(3μm 3.0x50mm)柱,以10mMpH10NH4HCO3/CH3CN为流动相(碱性系统)。使用Agilent 1100系列液相色谱/质量选择性检测器(Agilent 1100 Series Liquid Chromatograph/Mass Selective Detector)(MSD)进行电喷雾质谱(ES-MS)以获得靶分子的假分子(pseudo molecular)[M+H]+离子。制备型HPLC在Gilson 306 HPLC系统上进行,使用Kinetex C18(5μm,21x100mm)柱,以0.1%TFA/MilliQ H2O/CH3CN为流动相(酸性系统)或使用Gemini NX(5μm,21x100mm)柱,以50mM pH10NH4HCO3/CH3CN为流动相(碱性系统)。基于关注的化合物的最大波长下的UV信号收集级分。在Merck硅胶60(230-400目)或YMC凝胶S-150μm上进行制备型快速色谱。用BiotageInitiator仪器,使用配有铝盖和隔膜的0.5-2mL或2-5mL的Biotage工艺瓶(BiotageProcess Vial)进行微波反应。使用软件ACD Labs 10.0命名化合物。
中间体1
4,5-二氯吡啶-2-胺
向4-氯吡啶-2-胺(50.00g,0.389mol)在EtOAc(400mL)中的溶液中一次性添加N-氯琥珀酰亚胺(53.50g,0.401mol)。将混合物在室温下搅拌过夜(28h),然后过滤以除去沉淀的琥珀酰亚胺。将滤液用0.5M NaOH水溶液(8x50mL)、水(2x50mL)和盐水(2x50mL)洗涤。将有机相干燥(Na2SO4),过滤并蒸发以在真空干燥后提供59.4g的粗制浅棕色粉末。将干燥的分离的粗制品(纯度为约75%的标题化合物)在己烷(800mL)中制成浆并在回流温度下搅拌15min。让混合物冷却至35℃,然后用G3玻璃料过滤器过滤。滤饼用己烷(约200mL)洗涤并在过滤器上干燥以提供42.1g(66%)棕色固体。产物的纯度(96%)足以用于下一步骤。1HNMR(600MHz,DMSO-d6)δppm 8.02(s,1H)6.65(s,1H)6.42(s,2H).MS:(ESI+)m/z 163,165,167[M+H]+,二氯同位素模式。
中间体2
4,5-二氯-N-硝基吡啶-2-胺
将4,5-二氯吡啶-2-胺(中间体1,45.2g,283.0mmol)经约20分钟以多小份添加到270mL冰冷的浓H2SO4中。溶解时,滴加浓HNO3(22g),并将混合物在约5℃下搅拌3.5小时。LCMS表明完全转化为预期产物。将冷混合物倒在碎冰/水混合物(3L)上,搅拌约5分钟,然后过滤。收集固体并在冰冷的水(500mL)中制成浆并过滤。重复该程序直至中性pH。当在过滤器上半干时,将固体溶解在EtOAc(约3L)中,用盐水(约100mL)洗涤,有机层用Na2SO4干燥,过滤并蒸发,以提供46.2g(78%)的97%纯度标题产物,为米色-橙色固体。1H NMR(600MHz,CD3OD))δ(600MHz,CDaporated以提供46.2+)m/z 208,210,212[M+H]+,二氯同位素模式。
中间体3
4,5-二氯-3-硝基吡啶-2-胺
将4,5-二氯-N-硝基吡啶-2-胺(中间体2,20.0g,96.2mmol)在室温下添加到200mL浓H2SO4中。在40℃下搅拌2.5小时后,将混合物冷却至低于室温并在搅拌下倒在碎冰(2L)上。冰融化后,用冰冷的水将体积调节至约2L,通过过滤收集黄色沉淀,用冰冷的水洗涤至中性pH(3×250mL)。使固体在过滤器上半干,然后溶解在EtOAc(约800mL)中。将有机相用0.25M NaOH(3×30mL)、水(3×15mL)和盐水(15mL)洗涤,干燥(Na2SO4),过滤并蒸发溶剂,以提供11.7g(59%)99%纯度的标题产物,为黄色固体。1H NMR(600MHz,CD3OD)δppm8.26(s,1H).MS:(ESI+)m/z 208,210,212[M+H]+氯同位素模式。
中间体4
5-溴-4-氯吡啶-2-胺
标题产物通过与用于4,5-二氯吡啶-2-胺(中间体1)的程序相同的程序制备,除了将NCS换成NBS。1H NMR(600MHz,CD3OD)δppm8.03(s,1H)6.73(s,1H).MS(ESI+)m/z 207,209,211[M+H]+溴-氯同位素模式。
中间体5
5-溴-4-氯-N-硝基吡啶-2-胺
标题产物通过与用于4,5-二氯-N-硝基吡啶-2-胺(中间体2)的程序相同的程序制备。1H NMR(600MHz,CDCl3)δppm 8.49(s,1H)8.06(s,1H).MS(ESI+)m/z 252,254,256[M+H]+,溴-氯同位素模式。
中间体6
5-溴-4-氯-3-硝基吡啶-2-胺
标题产物通过与用于4,5-二氯-3-硝基吡啶-2-胺(中间体3)的程序相同的程序制备。1H NMR(600MHz,CDCl3)δppm 8.36(s,1H)5.82(br.s.,2H).MS(ESI+)m/z 252,254,256[M+H]+,溴-氯同位素模式。
中间体7
1-(4-甲氧基苄基)哌啶-4-胺
向4-boc-氨基哌啶(1001mg,5.0mmol)和4-甲氧基-苯甲醛(681mg,5.0mmol)在DCE(30mL)中的搅拌的混合物中添加NaBH(OAc)3(1696mg,8.0mmol)。将混合物在室温下搅拌20小时。添加饱和NaHCO3(10mL),并将混合物搅拌10分钟。将混合物用DCM(35mL)稀释,分离各相。用饱和NaHCO3(10mL)和盐水(8mL)洗涤有机相,经Na2SO4干燥并真空浓缩,产生1.503g(94%)[1-(4-甲氧基苄基)哌啶-4-基]氨基甲酸叔丁酯,为白色固体。1H NMR(600MHz,CD3OD)δppm 7.22(d,J=8.5Hz,2H)6.87(d,J=8.5Hz,2H)3.78(s,3H)3.45(s,2H)3.32-3.35(m,0H)2.84(d,J=11.6Hz,2H)2.09(t,J=11.6Hz,2H)1.83(d,J=11.6Hz,2H)1.44-1.51(m,2H)1.42(s,9H).MS(ESI+)m/z 321[M+H]+。
将前一步骤的产物溶于二噁烷(15mL)中。添加浓HCl(2mL,25mmol),并将反应混合物在室温下搅拌1.5小时。将混合物蒸发至小体积并添加水(10mL)。将得到的水相用EtOAc(15mL)洗涤。用8M NaOH将水相的pH调节至约pH12,然后用DCM(3×20mL)萃取。合并的有机相用盐水(5mL)洗涤,用Na2SO4干燥,最后蒸发,产生914mg(88%,两步)纯标题产物,为澄清的几乎无色油状物。1H NMR(600MHz,CD3OD)δppm 7.22(d,J=8.9Hz,2H)6.87(d,J=8.5Hz,2H)3.78(s,3H)3.44(s,2H)2.85(d,J=12.2Hz,2H)2.60(tt,J=10.7,4.3Hz,1H)2.04(td,J=11.9,2.1Hz,2H)1.79(d,J=13.1Hz,2H)1.39(dq,J=12.1,4.0Hz,2H).MS(ESI+)m/z 221[M+H]+。
中间体8
(3S)-1-(4-甲氧基苄基)吡咯烷-3-胺
根据用于中间体7的程序制备标题产物,使用(S)-3-boc-氨基吡咯烷代替4-boc-氨基哌啶。1H NMR(600MHz,CD3OD)δppm 7.24(d,J=8.9Hz,2H)6.87(d,J=8.9Hz,2H)3.78(s,3H)3.55(s,2H)3.40-3.45(m,1H)2.80(dd,J=9.9,6.9Hz,1H)2.67(td,J=8.9,6.3Hz,1H)2.54(ddd,J=9.5,8.2,6.1Hz,1H)2.27(dd,J=9.8,5.2Hz,1H)2.15-2.22(m,1H)1.47-1.54(m,1H).MS(ESI+)m/z 207[M+H]+。
中间体9
1-[4-(二甲基氨基)苄基]哌啶-4-胺
根据用于中间体7的程序制备标题产物,使用4-(二甲基氨基)苯甲醛代替4-甲氧基-苯甲醛。1H NMR(600MHz,CD3OD)δppm 7.14(d,J=8.5Hz,2H)6.74(d,J=8.9Hz,2H)3.41(s,2H)2.91(s,6H)2.86(d,J=12.2Hz,2H)2.57-2.65(m,1H)2.03(td,J=11.8,1.7Hz,2H)1.77-1.83(m,2H)1.40(qd,J=12.0,3.7Hz,2H).MS(ESI+)m/z 234[M+H]+。
中间体10
1-(2,3-二氢-1-苯并呋喃-5-基甲基)哌啶-4-胺
根据用于中间体7的程序制备标题产物,使用2,3-二氢-1-苯并呋喃-5-甲醛代替4-甲氧基-苯甲醛。1H NMR(600MHz,CD3OD)δppm7.16(s,1H)7.01(dd,J=8.1,1.7Hz,1H)6.66(d,J=7.9Hz,1H)4.52(t,J=8.7Hz,2H)3.42(s,2H)3.18(t,J=8.7Hz,2H)2.85(d,J=12.2Hz,2H)2.55-2.66(m,1H)2.03(t,J=11.9Hz,2H)1.75-1.83(m,2H)1.39(qd,J=12.0,3.8Hz,2H).MS(ESI+)m/z 233[M+H]+。
中间体11
1-(噻吩-2-基甲基)哌啶-4-胺
根据用于中间体7的程序制备标题产物,使用噻吩-2-甲醛代替4-甲氧基-苯甲醛。1HNMR(600MHz,CD3OD)δppm 7.31(dd,J=4.4,2.0Hz,1H)6.92-6.98(m,2H)3.73(s,2H)2.90(d,J=12.2Hz,2H)2.59(tt,J=10.7,4.3Hz,1H)2.09(td,J=11.9,2.1Hz,2H)1.77-1.85(m,2H)1.41(qd,J=12.0,3.8Hz,2H).MS(ESI+)m/z 197[M+H]+。
中间体12
1-(噻吩-3-基甲基)哌啶-4-胺
根据用于中间体7的程序制备标题产物,使用噻吩-3-甲醛代替4-甲氧基-苯甲醛。1HNMR(600MHz,CD3OD)δppm 7.36(dd,J=4.93,2.93Hz,1H)7.24(ddt,J=2.93,1.28,0.74Hz,1H)7.09(dd,J=4.93,1.28Hz,1H)3.56(s,2H)2.85-2.92(m,2H)2.65(tt,J=10.83,4.30Hz,1H)2.07(td,J=11.98,2.14Hz,2H)1.79-1.86(m,2H)1.39-1.48(m,2H).MS(ESI+)m/z 197[M+H]+。
中间体13
4-[(4-氨基哌啶-1-基)甲基]-2-甲氧基苯酚
根据用于中间体7的程序制备标题产物,使用4-羟基-3-甲氧基苯甲醛代替4-甲氧基-苯甲醛。1H NMR(600MHz,CD3OD)δppm 6.93-6.95(m,1H)6.74-6.76(m,2H)3.85(s,3H)3.53(s,2H)3.10(tt,J=11.52,4.27Hz,1H)2.98-3.05(m,2H)2.19(td,J=12.24,2.36Hz,2H)1.96-2.02(m,2H)1.62-1.71(m,2H).MS(ESI+)m/z 237[M+H]+。
中间体14
1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-胺
根据用于中间体7的程序制备标题产物,使用1,3,5-三甲基-1H-吡唑-4-甲醛代替4-甲氧基-苯甲醛。1H NMR(600MHz,DMSO-d6)δppm 3.59(s,3H)3.12(s,2H)2.65(d,J=11.6Hz,2H)2.43-2.49(m,1H)2.12(s,3H)2.02(s,3H)1.83(t,J=10.7Hz,2H)1.61(d,J=12.2Hz,2H)1.14(qd,J=11.6,2.6Hz,2H).MS(ESI+)m/z 223[M+H]+。
中间体15
1-乙基哌啶-4-胺
将4-Boc-氨基哌啶(1.95g,9.7mmol)和K2CO3(2.02g,7.5mmol)悬浮在CH3CN(20mL)中。将混合物在冰浴中冷却,滴加溶解在CH3CN(5mL)中的碘乙烷(1.67g,10.7mmol)。让混合物缓慢温热至室温并搅拌18小时。滤出固体,蒸发溶剂。将残余物溶于EtOAc(50mL)中,用水(3×6mL)和盐水(6mL)洗涤有机相,经Na2SO4干燥并蒸发至干,产生1.975g(89%)(1-乙基哌啶-4-基)氨基甲酸叔丁酯,为白色固体。1H NMR(600MHz,DMSO-d6)δppm 6.73(d,J=7.9Hz,1H)3.08-3.24(m,1H)2.77(d,J=11.6Hz,2H)2.26(q,J=7.1Hz,2H)1.83(t,J=11.1Hz,2H)1.66(d,J=11.3Hz,2H)1.37(s,9H)1.33(qd,J=11.9,3.4Hz,2H)0.96(t,J=7.2Hz,3H).MS(ESI+)m/z 229[M+H]+。
将前一步骤中分离的(1-乙基哌啶-4-基)氨基甲酸叔丁酯溶于二噁烷(15mL)中,添加浓HCl(2.5mL,31.3mmol)。将反应混合物在50℃下搅拌2.5小时。蒸发溶剂,将残余物溶解在MeOH中并蒸发两次。将得到的固体用Et2O研磨两次,然后在真空下干燥过夜,产生1.74g(99.8%)1-乙基哌啶-4-胺二盐酸盐,为灰白色固体。1H NMR(600MHz,CD3OD)δppm3.67-3.73(m,2H)3.50(tt,J=12.2,4.0Hz,1H)3.21(q,J=7.3Hz,2H)3.10(t,J=12.4Hz,2H)2.30(d,J=14.6Hz,2H)2.03(qd,J=13.1,3.1Hz,2H)1.38(t,J=7.3Hz,3H).MS(ESI+)m/z 129[M+H]+。
中间体16
1-(1-甲基乙基)哌啶-4-胺
根据用于中间体15的程序制备标题产物,使用2-溴-丙烷代替碘乙烷。分离产物,为二盐酸盐。1H NMR(600MHz,CD3OD)δppm 3.56-3.61(m,2H)3.56(spt,J=6.71Hz,1H)3.49(tt,J=12.10,4.31Hz,1H)3.19(td,J=13.08,2.20Hz,2H)2.27-2.34(m,2H)2.07(dddd,J=14.08,13.08,12.10,4.20Hz,2H)1.39(d,J=6.71Hz,6H).MS(ESI+)m/z 143[M+H]+。
中间体17
(3S)-1-甲基吡咯烷-3-胺
根据用于中间体15的程序制备标题产物,使用(S)-3-boc-氨基吡咯烷代替4-boc-氨基哌啶,用碘甲烷代替碘乙烷。分离产物,为二盐酸盐。1H NMR(600MHz,CD3OD)δppm(两种构象异构体)4.17-4.29(m,1H)4.05-4.18(m,2H)3.85-3.95(m,1H)3.74-3.86(m,2H)3.53-3.63(m,1H)3.40-3.51(m,1H)3.18-3.30(m,2H)3.06(br.s.,3H)3.00(br.s.,3H)2.65-2.78(m,1H)2.48-2.62(m,1H)2.25-2.37(m,1H)2.16-2.28(m,1H).MS(ESI+)m/z 101[M+H]+。
中间体18
(3S)-1-丙基吡咯烷-3-胺
根据用于中间体15的程序制备标题产物,使用(S)-3-boc-氨基吡咯烷代替4-boc-氨基哌啶,用碘丙烷代替碘乙烷。分离产物,为二盐酸盐。1H NMR(600MHz,CD3OD)δppm 3.39-4.32(m,4H)3.16-3.31(m,3H)2.45-2.79(m,1H)2.15-2.35(m,1H)1.76-1.85(m,2H)1.05(t,J=7.40Hz,3H).MS(ESI+)m/z 129[M+H]+。
中间体19
1-丙基哌啶-4-胺
根据用于中间体15的程序制备标题产物,使用1-碘丙烷代替碘乙烷。分离产物,为二盐酸盐。1H NMR(600MHz,CD3OD)δppm 3.67-3.73(m,2H)3.49(tt,J=12.00,3.90Hz,1H)3.12(td,J=13.20,2.50Hz,2H)3.06-3.11(m,2H)2.25-2.31(m,2H)2.03(dddd,J=13.70,13.20,12.00,4.20Hz,2H)1.77-1.85(m,2H)1.02(t,J=7.40Hz,3H).MS(ESI+)m/z 143[M+H]+。
中间体20
1-(2-甲氧基乙基)哌啶-4-胺
根据用于中间体15的程序制备标题产物,使用2-溴乙基甲基醚代替碘乙烷。分离产物,为二盐酸盐。1H NMR(600MHz,CD3OD)δppm 3.74-3.78(m,2H)3.72-3.77(m,2H)3.46-3.53(m,1H)3.41(s,3H)3.35-3.38(m,2H)3.20(td,J=13.20,2.29Hz,2H)2.25-2.31(m,2H)2.01-2.10(m,2H).MS(ESI+)m/z 159[M+H]+。
中间体21
1-环己基哌啶-4-胺
根据用于中间体7的程序制备标题产物,使用环己酮代替4-甲氧基-苯甲醛。1HNMR(600MHz,CD3OD)δppm 2.90(d,J=12.2Hz,2H)2.55-2.61(m,1H)2.25-2.34(m,3H)1.91(d,J=10.4Hz,2H)1.79-1.86(m,4H)1.65(d,J=13.1Hz,1H)1.38(qd,J=11.9,4.0Hz,2H)1.19-1.33(m,4H)1.09-1.18(m,1H).MS(ESI+)m/z 183[M+H]+。
中间体22
1-(环丙基甲基)哌啶-4-胺
根据用于中间体7的程序制备标题产物,使用环丙烷甲醛代替4-甲氧基-苯甲醛。1H NMR(600MHz,CD3OD)δppm 3.06(d,J=11.3Hz,2H)2.58-2.67(m,1H)2.25(d,J=6.7Hz,2H)2.08(t,J=11.4Hz,2H)1.81-1.87(m,2H)1.43(qd,J=12.0,3.7Hz,2H)0.85-0.92(m,1H)0.52-0.57(m,2H)0.11-0.17(m,2H).MS(ESI+)m/z 155[M+H]+。
中间体23
(4-氨基哌啶-1-基)乙腈
根据用于中间体15的程序制备标题产物,使用溴乙腈代替碘乙烷。反应在75℃进行17h。分离产物,为二盐酸盐。1H NMR(600MHz,CD3OD)δppm 4.39(s,2H)3.61-3.68(m,2H)3.46(tt,J=11.80,4.14Hz,1H)3.19(td,J=12.70,2.52Hz,2H)2.27-2.33(m,2H)2.01(dddd,J=13.80,12.70,11.80,4.20Hz,2H).MS(ESI+)m/z 140[M+H]+。
中间体24
3-(4-氨基哌啶-1-基)丙腈
根据用于中间体15的程序制备标题产物,使用溴丙腈代替碘乙烷。反应在75℃进行18.5h。分离产物,为二盐酸盐。1H NMR(600MHz,CD3OD)δppm 3.69-3.82(m,2H)3.46-3.60(m,3H)3.19-3.30(m,2H)3.14(t,J=7.25Hz,2H)2.27-2.34(m,2H)2.02-2.14(m,2H).MS(ESI+)m/z 154[M+H]+。
中间体25
5-氯-N4-[1-(4-甲氧基苄基)哌啶-4-基]-3-硝基吡啶-2,4-二胺
向4,5-二氯-3-硝基吡啶-2-胺(中间体3,3.71g,17.8mmol)在i-PrOH(50mL)中的浆液中添加1-(4-甲氧基苄基)哌啶-4-胺(中间体7,4.00g,18.17mmol)和DIPEA(5.7mL)。将混合物在50℃下搅拌过夜。让反应冷却至室温并离心。分离上清液,依次用EtOAc(25mL)、MeOH(2×25mL)、EtOAc(30mL)洗涤黄色固体,然后真空干燥,以提供6.70g(85%)99%纯度标题产物,为黄色粉末。1H NMR(600MHz,DMSO-d6)δppm 7.87(s,1H)7.76(d,J=6.41Hz,1H)7.57(br.s.,2H)7.19(d,J=8.55Hz,2H)6.87(d,J=8.85Hz,2H)3.83(br.s.,1H)3.73(s,3H)3.38(s,2H)2.67(d,J=9.46Hz,2H)2.03(t,J=10.38Hz,2H)1.87(dd,J=13.12,3.36Hz,2H)1.49-1.57(m,2H).MS(ESI+)m/z 392,394[M+H]+,氯同位素模式。
中间体26
5-溴-N4-[1-(4-甲氧基苄基)哌啶-4-基]-3-硝基吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用5-溴-4-氯-3-硝基吡啶-2-胺(中间体6)代替4,5-二氯-3-硝基吡啶-2-胺。1H NMR(600MHz,DMSO-d6)δppm 7.97(s,1H)7.42(s,2H)7.18(d,J=8.55Hz,2H)7.09(d,1H)6.86(d,2H)3.73(s,3H)3.67(br.s.,1H)3.37(s,2H)2.57-2.74(m,2H)1.95-2.08(m,2H)1.77-1.91(m,2H)1.36-1.59(m,2H).MS(ESI+)m/z 436,438[M+H]+,溴同位素模式。
中间体27
5-氯-N4-(1-甲基哌啶-4-基)-3-硝基吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-甲基哌啶-4-胺代替1-(4-甲氧基苄基)哌啶-4-胺。1H NMR(600MHz,DMSO-d6)δppm 7.88(s,1H)7.75(d,J=7.32Hz,1H)7.57(s,2H)3.72-3.85(m,1H)2.56-2.67(m,2H)2.14(s,3H)1.99(t,J=10.22Hz,2H)1.86(dd,J=12.82,3.66Hz,2H)1.54(dq,2H).MS(ESI+)m/z 286[M+H]+。
中间体28
5-溴-N4-(1-甲基哌啶-4-基)-3-硝基吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用5-溴-4-氯-3-硝基吡啶-2-胺(中间体6)代替4,5-二氯-3-硝基吡啶-2-胺,用1-甲基哌啶-4-胺代替1-(4-甲氧基苄基)哌啶-4-胺。1H NMR(600MHz,DMSO-d6)δppm 8.02(s,1H)7.45(br.s.,2H)6.93-7.14(m,1H)3.68-3.93(m,1H)3.33-3.46(m,2H)2.88-3.11(m,2H)2.70(br.s.,3H)2.06(d,J=13.73Hz,2H)1.70-1.93(m,2H).MS(ESI+)m/z 330,332[M+H]+,溴同位素模式。
中间体29
5-溴-N4-(1-乙基哌啶-4-基)-3-硝基吡啶-2,4-二胺
向5-溴-4-氯-3-硝基吡啶-2-胺(中间体6,1010mg,4.0mmol)在i-PrOH(15mL)中的浆液中添加1-乙基哌啶-4-胺二盐酸盐(中间体15,805mg,4.0mmol)和DIPEA(1.81g,14.0mmol,1.81mL)。将混合物在50℃搅拌19小时。让反应冷却至室温,离心并分离上清液。将固体在EtOAc(200mL)中制成浆并用饱和Na2CO3(2x20mL)洗涤。分离各相,有机相用水(3×15mL)和盐水(15mL)洗涤,经Na2SO4干燥,过滤并蒸发,产生1.166g(85%)纯标题产物,为亮黄色固体。1H NMR(600MHz,CD3OD)δppm 7.93(s,1H)3.99(br.s.,1H)2.87(br.s.,2H)2.45(q,J=7.3Hz,2H)2.17(br.s.,2H)2.00-2.09(m,2H)1.60(qd,J=11.2,3.4Hz,2H)1.11(t,J=7.3Hz,3H).MS(ESI+)m/z 344,346[M+H]+。
中间体30
5-氯-N4-(1-乙基哌啶-4-基)-3-硝基吡啶-2,4-二胺
根据用于中间体29的程序制备标题产物,使用4,5-二氯-3-硝基吡啶-2-胺(中间体3)代替5-溴-4-氯-3-硝基吡啶-2-胺。1H NMR(600MHz,CD3OD)δppm 7.81(s,1H)4.15(br.s.,1H)2.89(br.s.,2H)2.46(q,J=7.3Hz,2H)2.19(br.s.,2H)2.03-2.10(m,2H)1.62(qd,J=11.2,3.7Hz,2H)1.11(t,J=7.3Hz,3H).MS(ESI+)m/z 300[M+H]+。
中间体31
5-溴-3-硝基-N4-(1-丙基哌啶-4-基)吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用5-溴-4-氯-3-硝基吡啶-2-胺(中间体6)代替4,5-二氯-3-硝基吡啶-2-胺,用1-(1-甲基乙基)哌啶-4-胺二盐酸盐(中间体16)代替1-(4-甲氧基苄基)哌啶-4-胺。1H NMR(600MHz,CD3OD)δppm(主要构象异构体)8.01(s,1H)4.14-4.27(m,1H)3.45-3.60(m,3H)3.08-3.21(m,2H)2.32-2.43(m,2H)1.76-1.90(m,2H)1.37(d,J=6.71Hz,6H).MS(ESI+)m/z 358[M+H]+。
中间体32
5-氯-N4-[1-(1-甲基乙基)哌啶-4-基]-3-硝基吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-(1-甲基乙基)哌啶-4-胺二盐酸盐(中间体16)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,DMSO-d6)δppm7.83(br.s.,1H)3.51-4.01(br.m,1H)2.61-2.71(m,3H)2.16(t,J=10.30Hz,2H)1.70-1.94(br.m,2H)1.34-1.53(br.m,2H)0.93(d,J=6.56Hz,6H).MS(ESI+)m/z 314[M+H]+。
中间体33
5-氯-3-硝基-N4-{1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用4,5-二氯-3-硝基吡啶-2-胺(中间体3)和1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-胺(中间体14)。1H NMR(600MHz,DMSO-d6)δ7.87(s,1H)7.72(br.s.,1H)7.55(br.s.,2H)3.79(br.s.,1H)3.60(s,3H)3.16(br.s.,2H)2.65(br.s.,2H)2.13(s,3H)2.04(s,3H)1.97(br.s.,2H)1.85(d,J=9.5Hz,2H)1.48(q,J=10.1Hz,2H).MS(ESI+)m/z 394[M+H]+。
中间体34
5-氯-3-硝基-N4-[1-(噻吩-2-基甲基)哌啶-4-基]吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-(噻吩-2-基甲基)哌啶-4-胺(中间体11)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,DMSO-d6)δppm 7.87(s,1H)7.73(d,J=7.32Hz,1H)7.56(s,2H)7.41(dd,J=4.88,1.37Hz,1H)6.93-6.97(m,2H)3.76-3.86(m,1H)3.67(s,2H)2.68-2.79(m,2H)2.10(t,J=10.68Hz,2H)1.84-1.91(m,2H)1.50-1.60(m,2H).MS(ESI+)m/z 368[M+H]+。
中间体35
5-氯-3-硝基-N4-[1-(噻吩-3-基甲基)哌啶-4-基]吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-(噻吩-3-基甲基)哌啶-4-胺(中间体12)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,DMSO-d6)δppm 7.87(s,1H)7.76(d,J=7.02Hz,1H)7.57(s,2H)7.47(dd,J=4.94,2.94Hz,1H)7.27-7.30(m,J=2.94,1.24,0.80,0.80,0.80Hz,1H)7.02(dd,J=4.94,1.24Hz,1H)3.76-3.87(m,1H)3.46(s,2H)2.62-2.75(m,2H)2.05(t,J=10.22Hz,2H)1.84-1.91(m,2H)1.49-1.59(m,2H).MS(ESI+)m/z 368[M+H]+。
中间体36
5-氯-N4-{1-[4-(二甲基氨基)苄基]哌啶-4-基}-3-硝基吡啶-2,4-二胺根据用于中间体25的程序制备标题产物,使用1-[4-(二甲基氨基)苄基]哌啶-4-胺(中间体9)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,DMSO-d6)δppm 7.87(s,1H)7.76(d,J=5.49Hz,1H)7.57(s,2H)7.04-7.09(m,2H)6.64-6.68(m,2H)3.76-3.87(m,1H)3.32(s,2H)2.86(s,6H)2.60-2.73(m,2H)1.94-2.07(m,2H)1.82-1.90(m,2H)1.46-1.57(m,2H)。没有观察到亚甲基质子。它们很可能与DMSO峰重叠。MS(ESI+)m/z 405[M+H]+。
中间体37
4-({4-[(2-氨基-5-氯-3-硝基吡啶-4-基)氨基]哌啶-1-基}甲基)-2-甲氧基苯酚
根据用于中间体25的程序制备标题产物,使用4-[(4-氨基哌啶-1-基)甲基]-2-甲氧基苯酚(中间体13)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。然而,后处理程序不同。蒸发全部反应混合物,将粗制固体用EtOAc研磨一次,用MeOH研磨三次。将得到的固体真空干燥,产生约70%纯度的标题产物,将其不经进一步纯化用于下一步骤。
MS(ESI+)m/z 408[M+H]+。
中间体38
5-氯-N4-[1-(2,3-二氢-1-苯并呋喃-5-基甲基)哌啶-4-基]-3-硝基吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-(2,3-二氢-1-苯并呋喃-5-基甲基)哌啶-4-胺(中间体10)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,DMSO-d6)δppm 7.87(s,1H)7.76(d,J=5.80Hz,1H)7.57(s,2H)7.13(br.s.,1H)6.96(d,J=7.93Hz,1H)6.67(d,J=7.93Hz,1H)4.49(t,J=8.66Hz,2H)3.76-3.89(m,1H)3.35(br.s.,2H)3.14(t,J=8.66Hz,2H)2.62-2.73(m,2H)1.96-2.11(m,2H)1.82-1.91(m,2H)1.47-1.59(m,2H).MS(ESI+)m/z 404[M+H]+。
中间体39
5-氯-N4-[(3S)-1-甲基吡咯烷-3-基]-3-硝基吡啶-2,4-二胺
向4,5-二氯-3-硝基吡啶-2-胺(中间体3,1.20g,5.78mmol)在i-PrOH(16mL)中的浆液中添加(3S)-1-甲基吡咯烷-3-胺二盐酸盐(中间体17,1.00g,5.78mmol)和DIPEA(2.48g,19.07mmol,3.5mL)。将混合物在50℃下搅拌过夜。将混合物冷却至室温并在G3玻璃过滤器上过滤。用IPA(3×5mL)洗涤固体物质并真空干燥。然后将固体溶解在EtOAc(150mL)中,并用饱和K2CO3水溶液(2x8mL)、盐水(8mL)洗涤并干燥(Na2SO4)。过滤有机相,蒸发溶剂,以提供735mg(53%)98%纯度标题产物,为黄色固体。1H NMR(600MHz,DMSO-d6)δppm 8.13(d,J=7.32Hz,1H)7.86(s,1H)7.59(s,2H)4.38-4.49(m,1H)2.71-2.77(m,1H)2.60(dd,J=9.92,2.90Hz,1H)2.52(d,J=6.00Hz,1H)2.25(s,3H)2.17-2.24(m,2H)1.68-1.73(m,1H).MS(ESI+)m/z272[M+H]+。
中间体40
5-溴-N4-[(3S)-1-甲基吡咯烷-3-基]-3-硝基吡啶-2,4-二胺
根据用于中间体39的程序制备标题产物,使用5-溴-4-氯-3-硝基吡啶-2-胺(中间体6)代替4,5-二氯-3-硝基吡啶-2-胺。1H NMR(600MHz,DMSO-d6)δppm 7.96(s,1H)7.41(s,2H)7.36-7.40(m,1H)4.18-4.29(m,1H)2.70-2.79(m,1H)2.58(dd,J=9.77,2.75Hz,1H)2.48(d,J=6.10Hz,1H)2.25(s,3H)2.15-2.23(m,2H)1.61-1.73(m,1H).MS(ESI+)m/z 316[M+H]+。
中间体41
5-氯-3-硝基-N4-[(3S)-1-丙基吡咯烷-3-基]吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用(3S)-1-丙基吡咯烷-3-胺二盐酸盐(中间体18)代替1-(4-甲氧基苄基)哌啶-4-胺。MS(ESI+)m/z 300[M+H]+。
中间体42
5-氯-N4-[(3S)-1-(4-甲氧基苄基)吡咯烷-3-基]-3-硝基吡啶-2,4-二胺
根据用于中间体29的程序制备标题产物,使用4,5-二氯-3-硝基吡啶-2-胺(中间体3)和(3S)-1-(4-甲氧基苄基)吡咯烷-3-胺(中间体8)。1H NMR(600MHz,CD3OD)δppm 7.78(s,1H)7.23-7.27(m,2H)6.85-6.89(m,2H)4.61-4.68(m,1H)3.78(s,3H)3.62(d,J=12.67Hz,1H)3.57(d,J=12.67Hz,1H)2.86-2.92(m,1H)2.67-2.74(m,2H)2.33-2.44(m,2H)1.78-1.84(m,1H).MS(ESI+)m/z 378[M+H]+。
中间体43
5-氯-3-硝基-N4-(1-丙基哌啶-4-基)吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-丙基哌啶-4-胺(中间体19)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,CD3OD)δppm 7.88(s,1H)4.26-4.45(br.m,1H)3.38-3.71(br.m,2H)2.99-3.08(m,2H)2.94-3.21(br.m,2H)2.22-2.40(br.m,2H)1.76-1.96(br.m,2H)1.71-1.80(m,2H)1.02(t,J=7.40Hz,3H).MS(ESI+)m/z 314[M+H]+。
中间体44
5-溴-3-硝基-N4-(1-丙基哌啶-4-基)吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-丙基哌啶-4-胺(中间体19)和5-溴-4-氯-3-硝基吡啶-2-胺(中间体6)。1H NMR(600MHz,CD3OD,两种构象异构体)δppm 8.00(s,2H)4.10-4.29(m,2H)3.49-3.73(m,4H)2.85-3.24(m,8H)2.26-2.40(m,2H)2.21-2.28(m,2H)1.92-2.03(m,2H)1.77-1.94(m,2H)1.73-1.81(m,4H)1.03(t,J=7.40Hz,3H)1.02(t,J=7.40Hz,3H).MS(ESI+)m/z 358,360[M+H]+。
中间体45
5-氯-N4-[1-(2-甲氧基乙基)哌啶-4-基]-3-硝基吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-(2-甲氧基乙基)哌啶-4-胺(中间体20)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,CD3OD)δppm 7.89(s,1H)4.29-4.38(m,1H)3.69-3.76(m,2H)3.62-3.71(m,2H)3.42(s,3H)3.31-3.37(m,2H)3.10-3.20(m,2H)2.30-2.40(m,2H)1.77-1.93(m,2H).MS(ESI+)m/z330[M+H]+。
中间体46
5-氯-N4-(1-环己基哌啶-4-基)-3-硝基吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-环己基哌啶-4-胺(中间体21)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,DMSO-d6)δppm 7.88(s,1H)7.75(d,J=8.09Hz,1H)7.57(s,2H)3.77-3.87(m,1H)2.69-2.79(m,2H)2.20-2.34(m,3H)1.84-1.91(m,2H)1.66-1.76(m,4H)1.53-1.59(m,1H)1.44-1.53(m,2H)1.11-1.23(m,4H)1.00-1.10(m,1H).MS(ESI+)m/z 354[M+H]+。
中间体47
5-溴-3-硝基-N4-(1,2,2,6,6-五甲基哌啶-4-基)吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用可商购获得的4-氨基-1,2,2,6,6-五甲基哌啶和5-溴-4-氯-3-硝基吡啶-2-胺(中间体6)。1H NMR(600MHz,DMSO-d6)δppm 7.97(s,1H)7.35(s,2H)6.85(d,J=6.87Hz,1H)3.84-3.94(m,1H)2.15(s,3H)1.77(dd,J=11.75,2.44Hz,2H)1.35(t,J=11.75Hz,2H)1.06(s,6H)0.97(s,6H).MS(ESI+)m/z 386[M+H]+。
中间体48
5-氯-3-硝基-N4-(1,2,2,6,6-五甲基哌啶-4-基)吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用可商购获得的4-氨基-1,2,2,6,6-五甲基哌啶和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,DMSO-d6)δppm 7.88(s,1H)7.50(br.s.,3H)3.98-4.08(m,1H)2.16(br.s.,3H)1.77-1.85(m,2H)1.31-1.43(m,2H)1.07(br.s.,6H)0.98(br.s.,6H).MS(ESI+)m/z 342[M+H]+。
中间体49
5-氯-N4-[1-(环丙基甲基)哌啶-4-基]-3-硝基吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-(环丙基甲基)哌啶-4-胺(中间体22)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,CD3OD)δppm 7.81(s,1H)4.15(br.s.,1H)3.01(br.s.,2H)2.29(d,J=6.7Hz,2H)2.25(br.s.,2H)2.04-2.11(m,2H)1.60-1.70(m,2H)0.85-0.93(m,1H)0.53-0.58(m,2H)0.13-0.17(m,2H).MS(ESI+)m/z 326[M+H]+。
中间体50
5-溴-N4-[1-(环丙基甲基)哌啶-4-基]-3-硝基吡啶-2,4-二胺
根据用于中间体25的程序制备标题产物,使用1-(环丙基甲基)哌啶-4-胺(中间体22)和5-溴-4-氯-3-硝基吡啶-2-胺(中间体6)。1H NMR(600MHz,CD3OD)δppm 7.94(s,1H)3.98(br.s.,1H)3.00(br.s.,2H)2.29(d,J=6.7Hz,2H)2.23(br.s.,2H)2.02-2.08(m,2H)1.58-1.67(m,2H)0.84-0.93(m,1H)0.50-0.60(m,2H)0.10-0.20(m,2H).MS(ESI+)m/z 370,372[M+H]+。
中间体51
{4-[(2-氨基-5-氯-3-硝基吡啶-4-基)氨基]哌啶-1-基}乙腈
根据用于中间体25的程序制备标题产物,使用(4-氨基哌啶-1-基)乙腈(中间体23)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,DMSO-d6)δppm 7.89(s,1H)7.70(d,J=7.48Hz,1H)7.58(s,2H)3.73-3.82(m,1H)3.72(s,2H)2.68-2.78(m,2H)2.19-2.29(m,2H)1.88-1.96(m,2H)1.54-1.64(m,2H).MS(ESI+)m/z 311[M+H]+。
中间体52
{4-[(2-氨基-5-溴-3-硝基吡啶-4-基)氨基]哌啶-1-基}乙腈
根据用于中间体25的程序制备标题产物,使用(4-氨基哌啶-1-基)乙腈(中间体23)和5-溴-4-氯-3-硝基吡啶-2-胺(中间体6)。1H NMR(600MHz,DMSO-d6)δppm 7.98(s,1H)7.45(s,2H)7.13(d,J=8.39Hz,1H)3.72(s,2H)3.60-3.69(m,1H)2.69-2.77(m,2H)2.18-2.26(m,2H)1.86-1.94(m,2H)1.53-1.63(m,2H).MS(ESI+)m/z 355[M+H]+。
中间体53
3-{4-[(2-氨基-5-氯-3-硝基吡啶-4-基)氨基]哌啶-1-基}丙腈
根据用于中间体25的程序制备标题产物,使用3-(4-氨基哌啶-1-基)丙腈(中间体24)和4,5-二氯-3-硝基吡啶-2-胺(中间体3)。1H NMR(600MHz,DMSO-d6)δppm 7.88(s,1H)7.72(d,J=8.85Hz,1H)7.57(s,2H)3.72-3.84(m,1H)2.70-2.81(m,2H)2.65(dd,J=7.02,6.41Hz,2H)2.55(dd,J=7.02,6.41Hz,2H)2.05-2.15(m,2H)1.84-1.91(m,2H)1.49-1.59(m,2H).MS(ESI+)m/z 325[M+H]+。
中间体54
3-{4-[(2-氨基-5-溴-3-硝基吡啶-4-基)氨基]哌啶-1-基}丙腈
根据用于中间体25的程序制备标题产物,使用3-(4-氨基哌啶-1-基)丙腈(中间体24)和5-溴-4-氯-3-硝基吡啶-2-胺(中间体6)。1H NMR(600MHz,DMSO-d6)δppm 7.98(s,1H)7.43(s,2H)7.09(d,J=8.54Hz,1H)3.58-3.68(m,1H)2.70-2.80(m,2H)2.65(dd,J=7.02,6.41Hz,2H)2.54(dd,J=7.02,6.41Hz,2H)2.04-2.14(m,2H)1.82-1.88(m,2H)1.49-1.58(m,2H).MS(ESI+)m/z 369[M+H]+。
中间体55
4-[4-(2-羟基乙基)哌嗪-1-基]苯甲醛
向4-氟苯甲醛(1.24g,10mmol)在水(10mL)中的搅拌的溶液中添加2-哌嗪-1-基乙醇(1.95g,15mmol)和碳酸钾(2.76g,20mmol),并且将混合物在100℃下搅拌12小时。让反应混合物冷却至室温,通过过滤分离形成的沉淀。将滤饼用水洗涤并真空干燥,提供2.29g(98%)99%纯度标题产物,为灰白色固体。1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=9.2Hz,2H)7.04(d,J=9.2Hz,2H)4.44(br.s.,1H)3.54(t,J=5.6Hz,2H)3.37(t,J=5.2Hz,4H)2.53(t,J=5.2Hz,4H)2.43(t,J=6.3Hz,2H).MS(ESI+)m/z 235[M+H]+。
中间体56
4-[4-(2-甲氧基乙基)哌嗪-1-基]苯甲醛
根据用于中间体55的程序制备标题产物,使用1-(2-甲氧基乙基)哌嗪代替2-哌嗪-1-基乙醇。将反应混合物用DCM(2×30mL)萃取,并将合并的有机相用水(2×30mL)洗涤,用Na2SO4干燥,并真空浓缩,产生纯的标题产物,为浅棕色油状物,静置后固化。1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=9.2Hz,2H)7.04(d,J=8.9Hz,2H)3.47(t,J=5.8Hz,2H)3.37(t,J=5.2Hz,4H)3.24(s,3H)2.53(t,J=5.2Hz,4H)2.52(t,J=5.8Hz,2H).MS(ESI+)m/z 249[M+H]+。
中间体57
4-(4-乙基哌嗪-1-基)苯甲醛
根据用于中间体56的程序制备标题产物,使用1-乙基哌嗪代替1-(2-甲氧基乙基)哌嗪。1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=8.9Hz,2H)7.04(d,J=8.9Hz,2H)3.38(t,J=5.2Hz,4H)2.47(t,J=4.9Hz,4H)2.36(q,J=7.3Hz,2H)1.03(t,J=7.2Hz,3H).MS(ESI+)m/z 219[M+H]+。
中间体58
4-(4-吡啶-4-基哌嗪-1-基)苯甲醛
根据用于中间体56的程序制备标题产物,使用1-吡啶-4-基哌嗪代替1-(2-甲氧基乙基)哌嗪。1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)8.18(d,J=6.4Hz,2H)7.74(d,J=8.9Hz,2H)7.07(d,J=9.2Hz,2H)6.84(d,J=6.7Hz,2H)3.55-3.59(m,4H)3.48-3.53(m,4H).MS(ESI+)m/z 268[M+H]+。
中间体59
4-吗啉-4-基苯甲醛
根据用于中间体56的程序制备标题产物,使用吗啉代替1-(2-甲氧基乙基)哌嗪。1H NMR(600MHz,DMSO-d6)δppm 9.74(s,1H)7.73(d,J=9.2Hz,2H)7.06(d,J=8.9Hz,2H)3.73(t,J=4.9Hz,4H)3.34(t,J=4.9Hz,4H).MS(ESI+)m/z 192[M+H]+。
中间体60
4-(4-乙酰基哌嗪-1-基)苯甲醛
根据用于中间体56的程序制备标题产物,使用1-乙酰基哌嗪代替1-(2-甲氧基乙基)哌嗪。通过用i-PrOH研磨然后通过快速色谱法(二氧化硅,0-2%MeOH/DCM)纯化粗制产物。1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)7.73(d,J=8.9Hz,2H)7.05(d,J=8.9Hz,2H)3.58(dt,J=6.8,3.5Hz,4H)3.47(t,J=5.5Hz,2H)3.40(t,J=5.5Hz,2H)2.04(s,3H).MS(ESI+)m/z 233[M+H]+。
中间体61
4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯甲醛
根据用于中间体56的程序制备标题产物,使用1-甲基-1,4-二氮杂环庚烷代替1-(2-甲氧基乙基)哌嗪。1H NMR(600MHz,DMSO-d6)δppm 9.64(s,1H)7.66(d,J=8.9Hz,2H)6.83(d,J=8.9Hz,2H)3.61(t,J=4.9Hz,2H)3.54(t,J=6.3Hz,2H)2.61(t,J=4.9Hz,2H)2.44(t,J=5.5Hz,2H)2.25(s,3H)1.89(ddd,J=11.7,6.1,6.0Hz,2H).MS(ESI+)m/z 219[M+H]+。
中间体62
4-(3-氧代哌嗪-1-基)苯甲醛
根据用于中间体56的程序制备标题产物,使用哌嗪-2-酮代替1-(2-甲氧基乙基)哌嗪.粗制产物通过快速色谱(二氧化硅,2-3%MeOH/DCM)纯化。1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)8.20(br.s.,1H)7.73(d,J=8.9Hz,2H)7.00(d,J=8.9Hz,2H)3.92(s,2H)3.60(dd,J=6.1,4.6Hz,2H)3.33(dd,J=6.1,4.6Hz,2H).MS(ESI+)m/z 205[M+H]+。
中间体63
1-(甲基磺酰基)哌嗪
将甲磺酰氯(1.20g,10.5mmol)/DCM(10mL)滴加至boc-哌嗪(1.86g,10mmol)在DCM(35mL)和Et3N(2.02g,20mmol,2.79mL)中的溶液中。将混合物在室温下搅拌1,5h。有机相用水(2x8mL)和盐水(8mL)洗涤,经Na2SO4干燥。蒸发溶剂以产生2.66g(定量)4-(甲基磺酰基)哌嗪-1-甲酸叔丁酯,为白色固体。1H NMR(600MHz,CD3OD)δppm 3.53(br.s.,4H)3.18(t,J=5.2Hz,4H)2.84(s,3H)1.47(s,9H).MS(ESI+)m/z 165[M+H-t-Boc]+。
将粗制的4-(甲基磺酰基)哌嗪-1-甲酸叔丁酯溶于二噁烷(20mL)中并添加浓HCl(2mL,25mmol)。将反应混合物在室温下搅拌3小时,然后在50℃下搅拌1小时。让混合物冷却至室温,蒸发溶剂。剩余的固体用Et2O研磨,除去上清液后,将固体真空干燥,产生1.90g(95%)标题产物,为盐酸盐。1H NMR(600MHz,DMSO-d6)δppm 9.31(br.s.,1H)3.36(t,J=5.5Hz,4H)3.18(t,J=5.2Hz,4H)2.99(s,3H).MS(ESI+)m/z 165[M+H]+。
中间体64
4-[4-(甲基磺酰基)哌嗪-1-基]苯甲醛
根据用于中间体56的程序制备标题产物,使用1-(甲基磺酰基)哌嗪盐酸盐(中间体63)代替1-(2-甲氧基乙基)哌嗪,用3当量的碳酸钾代替2当量的碳酸钾。粗制产物通过快速色谱纯化(二氧化硅,40-60%EtOAc/正己烷)。1H NMR(600MHz,DMSO-d6)δppm 9.74(s,1H)7.74(d,J=8.9Hz,2H)7.10(d,J=8.9Hz,2H)3.53(t,J=5.2Hz,4H)3.23(t,J=5.2Hz,4H)2.92(s,3H).MS(ESI+)m/z 269[M+H]+。
中间体65
4-(5-氧代-1,4-二氮杂环庚烷-1-基)苯甲醛
根据用于中间体56的程序制备标题产物,使用[1,4]二氮杂环庚烷-5-酮代替1-(2-甲氧基乙基)哌嗪。粗制产物通过快速色谱纯化(二氧化硅,2-4%MeOH/DCM)。1H NMR(600MHz,DMSO-d6)δppm9.69(s,1H)7.71(d,J=9.2Hz,2H)7.62(t,J=5.0Hz,1H)6.98(d,J=8.9Hz,2H)3.71(dt,J=5.5,2.7Hz,2H)3.65-3.69(m,2H)3.22(ddd,J=7.5,5.5,1.7Hz,2H)2.53(dt,J=5.5,2.7Hz,2H).MS(ESI+)m/z 219[M+H]+。
中间体66
4-[4-(2-乙氧基乙基)哌嗪-1-基]苯甲醛
将1-Boc-哌嗪(1.86g,10.0mmol)、2-溴乙基乙基醚(1.92g,12.5mmol)和K2CO3(2.07g,15.0mmol)在CH3CN(25mL)中在70℃搅拌19h。让混合物冷却至室温。滤出固体,滤液用EtOAc(60mL)稀释。有机相用水(6mL)和盐水(6mL)洗涤,经Na2SO4干燥,蒸发以产生2.45g(95%)4-(2-乙氧基乙基)哌嗪-1-甲酸叔丁酯。1H NMR(600MHz,DMSO-d6)δppm 3.46(t,J=6.0Hz,2H)3.40(q,J=7.0Hz,2H)3.28(br.s.,4H)2.46(t,J=6.0Hz,2H)2.34(t,J=5.2Hz,4H)1.39(s,9H)1.09(t,J=7.0Hz,3H).MS(ESI+)m/z 259[M+H]+。
将产物溶于二噁烷(20mL)中并添加浓HCl(3.2mL,40mmol)。将混合物在室温下搅拌1小时,然后在60℃下搅拌0.5小时。将反应混合物真空浓缩,产生2.10g(96%)1-(2-乙氧基乙基)哌嗪,为二盐酸盐。1H NMR(600MHz,CD3OD)δppm 3.83-3.86(m,2H)3.60(q,J=7.0Hz,2H)3.64(br.s.,8H)3.50-3.53(m,2H)1.24(t,J=7.0Hz,3H).MS(ESI+)m/z 159[M+H]+。
向4-氟苯甲醛(1.69g,13.6mmol)在水(15mL)中的搅拌的溶液中添加1-(2-乙氧基乙基)哌嗪二盐酸盐(2.10g,9.08mmol)和碳酸钾(5.02g,36.3mmol),将混合物在100℃下搅拌15小时。让反应混合物冷却至室温并用DCM(3×25mL)萃取。蒸发合并的有机萃取物,产生2.80g粗制产物,将其通过快速色谱(二氧化硅,2%MeOH/DCM)纯化。合并纯级分并蒸发,产生1.68g(71%)纯标题产物,为浅黄色油状物。1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=8.9Hz,2H)7.04(d,J=8.9Hz,2H)3.51(t,J=6.0Hz,2H)3.43(q,J=7.0Hz,2H)3.37(t,J=5.2Hz,4H)2.54(t,J=5.2Hz,4H)2.51(t,J=6.0Hz,2H)1.11(t,J=7.0Hz,3H).MS(ESI+)m/z 263[M+H]+。
中间体67
4-[4-(2-甲氧基乙基)-1,4-二氮杂环庚烷-1-基]苯甲醛
根据用于中间体66的程序制备标题产物,使用1-boc-高哌嗪代替1-boc-哌嗪,用2-溴乙基甲基醚代替2-溴乙基乙基醚。
4-(2-甲氧基乙基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 3.38(t,J=6.0Hz,2H)3.30-3.35(m,4H)3.22(s,3H)2.54-2.66(m,6H)1.65-1.71(m,2H)1.39(s,9H).MS(ESI+)m/z 259[M+H]+。
1-(2-甲氧基乙基)-1,4-二氮杂环庚烷二盐酸盐:1H NMR(600MHz,CD3OD)δppm3.76(t,J=4.9Hz,2H)3.70(br.s.,2H)3.49(t,J=5.2Hz,2H)3.44-3.47(m,2H)3.43(s,3H)3.39-3.89(m,4H)2.31(ddd,J=10.5,5.5,5.3Hz,2H).MS(ESI+)m/z 159[M+H]+。
4-[4-(2-甲氧基乙基)-1,4-二氮杂环庚烷-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.64(s,1H)7.66(d,J=9.2Hz,2H)6.83(d,J=8.9Hz,2H)3.58(t,J=5.2Hz,2H)3.55(t,J=6.3Hz,2H)3.38(t,J=6.0Hz,2H)3.21(s,3H)2.77(t,J=5.2Hz,2H)2.62(t,J=6.0Hz,2H)2.56(t,J=5.8Hz,2H)1.84(dt,J=11.8,5.8Hz,2H).MS(ESI+)m/z 263[M+H]+。
中间体68
4-[4-(2-乙氧基乙基)-1,4-二氮杂环庚烷-1-基]苯甲醛
根据用于中间体66的程序制备标题产物,使用1-boc-高哌嗪代替1-boc-哌嗪。
4-(2-乙氧基乙基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 3.56(t,J=5.3Hz,2H)3.50(q,J=7.0Hz,2H)3.42-3.48(m,4H)2.75-2.78(m,2H)2.68-2.74(m,4H)1.83(sxt,J=6.0Hz,2H)1.46(s,9H)1.18(t,J=7.0Hz,3H).MS(ESI+)m/z 273[M+H]+。
1-(2-乙氧基乙基)-1,4-二氮杂环庚烷二盐酸盐:1H NMR(600MHz,CD3OD)δppm3.93(br.s.,1H)3.82(t,J=4.4Hz,2H)3.77(br.s.,2H)3.73(br.s.,2H)3.60(q,J=7.0Hz,2H)3.50(t,J=4.9Hz,2H)3.48-3.50(m,2H)3.38-3.47(m,2H)2.30-2.36(m,2H)1.24(t,J=7.0Hz,3H).MS(ESI+)m/z 173[M+H]+。
4-[4-(2-乙氧基乙基)-1,4-二氮杂环庚烷-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.64(s,1H)7.66(d,J=9.2Hz,2H)6.82(d,J=9.2Hz,2H)3.58(t,J=5.2Hz,2H)3.55(t,J=6.3Hz,2H)3.42(t,J=6.1Hz,2H)3.38(q,J=7.0Hz,2H)2.78(t,J=5.2Hz,2H)2.61(t,J=6.1Hz,2H)2.57(t,J=5.5Hz,2H)1.84(dt,J=11.8,5.8Hz,2H)1.07(t,J=7.0Hz,3H).MS(ESI+)m/z 277[M+H]+。
中间体69
2-(1-甲基乙氧基)乙基甲烷磺酸酯
向2-(1-甲基乙氧基)乙醇(2.83g,20mmol)和三乙基胺(4.05g,40mmol,5.58mL)在DCM(30mL)中的搅拌的溶液中在冰浴温度下滴加甲磺酰氯(2.52g,22mmol,1.1eq)在DCM(10mL)中的溶液。在室温下搅拌1.5小时后,有机相用水(2x8mL)和盐水(8mL)洗涤。有机相经MgSO4干燥,过滤并蒸发溶剂,以产生3.645g(100%)标题产物,为澄清的浅琥珀色液体。1HNMR(600MHz,CD3OD)δppm 4.31-4.34(m,2H)3.69-3.71(m,2H)3.67(spt,J=6.1Hz,1H)3.09(s,3H)1.17(d,J=6.4Hz,6H).MS(ESI+)m/z 183[M+H]+。
中间体70
4-{4-[2-(1-甲基乙氧基)乙基]哌嗪-1-基}苯甲醛
根据用于中间体66的程序制备标题产物,使用2-(1-甲基乙氧基)乙基甲烷磺酸酯(中间体69)代替2-溴乙基乙基醚。
4-[2-(1-甲基乙氧基)乙基]哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm3.51(spt,J=6.1Hz,1H)3.45(t,J=6.1Hz,2H)3.28(br.s.,4H)2.44(t,J=6.1Hz,2H)2.35(t,J=5.2Hz,4H)1.39(s,9H)1.06(d,J=6.1Hz,6H).MS(ESI+)m/z 273[M+H]+。
1-[2-(1-甲基乙氧基)乙基]哌嗪:1H NMR(600MHz,DMSO-d6)δppm 3.50(spt,J=6.0Hz,1H)3.43(t,J=6.3Hz,2H)2.64(t,J=4.9Hz,4H)2.37(t,J=6.3Hz,2H)2.30(br.s.,4H)1.06(d,J=5.8Hz,6H).MS(ESI+)m/z 173[M+H]+。
4-{4-[2-(1-甲基乙氧基)乙基]哌嗪-1-基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.71(s,1H)7.70(d,J=8.9Hz,2H)7.04(d,J=8.9Hz,2H)3.54(spt,J=6.1Hz,1H)3.50(t,J=6.0Hz,2H)3.36(t,J=5.2Hz,4H)2.54(t,J=4.9Hz,4H)2.50(t,J=5.9Hz,2H)1.08(d,J=6.1Hz,6H).MS(ESI+)m/z 277[M+H]+。
中间体71
4-{4-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷-1-基}苯甲醛
根据用于中间体66的程序制备标题产物,使用1-boc-高哌嗪代替1-boc-哌嗪,用2-(1-甲基乙氧基)乙基甲烷磺酸酯(中间体69)代替2-溴乙基乙基醚。
4-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 3.51(spt,J=6.1Hz,1H)3.42(t,J=6.1Hz,2H)3.29-3.35(m,4H)2.61-2.67(m,2H)2.55-2.61(m,4H)1.64-1.71(m,2H)1.39(s,9H)1.06(d,J=6.1Hz,6H).MS(ESI+)m/z287[M+H]+。
1-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷:1H NMR(600MHz,CD3OD)δppm3.60(spt,J=6.1Hz,1H)3.57(t,J=5.8Hz,2H)2.91-2.96(m,4H)2.79-2.83(m,4H)2.73(t,J=5.8Hz,2H)1.80-1.86(m,2H)1.15(d,J=6.1Hz,6H).MS(ESI+)m/z 187[M+H]+。
4-{4-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷-1-基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.64(s,1H)7.65(d,J=9.2Hz,2H)6.82(d,J=8.9Hz,2H)3.58(t,J=5.2Hz,2H)3.55(t,J=6.1Hz,2H)3.49(spt,J=6.1Hz,1H)3.41(t,J=6.3Hz,2H)2.78(t,J=5.2Hz,2H)2.59(t,J=6.3Hz,2H)2.57(t,J=5.5Hz,2H)1.84(quin,J=6.0Hz,2H)1.05(d,J=6.1Hz,6H).MS(ESI+)m/z 291[M+H]+。
中间体72
4-[4-(3-甲氧基丙基)哌嗪-1-基]苯甲醛
根据用于中间体66的程序制备标题产物,使用3-溴丙基甲基醚代替2-溴乙基乙基醚。
4-(3-甲氧基丙基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 3.32(t,J=6.4Hz,2H)3.28(br.s.,4H)3.20(s,3H)2.30(t,J=7.3Hz,2H)2.27(t,J=5.0Hz,4H)1.64(dt,J=14.9,6.4Hz,2H)1.39(s,9H).MS(ESI+)m/z 259[M+H]+。
1-(3-甲氧基丙基)哌嗪:1H NMR(600MHz,DMSO-d6)δppm 3.31(t,J=6.6Hz,2H)3.20(s,3H)2.67(t,J=4.9Hz,4H)2.26(br.s.,4H)2.24(t,J=7.3Hz,2H)1.62(dt,J=14.6,6.9Hz,2H).MS(ESI+)m/z 159[M+H]+。
4-[4-(3-甲氧基丙基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=9.2Hz,2H)7.04(d,J=9.2Hz,2H)3.37(t,J=5.2Hz,4H)3.36(t,J=6.6Hz,2H)3.22(s,3H)2.47(t,J=5.2Hz,4H)2.35(t,J=7.5Hz,2H)1.69(dt,J=14.6,6.4Hz,2H).MS(ESI+)m/z 263[M+H]+。
中间体73
2-(2-甲氧基乙氧基)乙基甲烷磺酸酯
向二乙二醇单甲醚(2.4g,20mmol)和三乙基胺(4.05g,40mmol,5.5mL)在DCM(30mL)中的搅拌的溶液中滴加甲磺酰氯(2.52g,22mmol,1.1eq.)在DCM(10mL)中的冰冷的溶液。让混合物在室温下搅拌3小时。将有机相用水(4x8mL)和盐水(10mL)洗涤,用Na2SO4干燥。蒸发溶剂以提供3.71g(94%)产物,为澄清的浅琥珀色油状物。1H NMR(600MHz,DMSO-d6)δppm 4.28-4.32(m,2H)3.64-3.68(m,2H)3.54-3.58(m,2H)3.43-3.47(m,2H)3.25(s,3H)3.18(s,3H).MS(ESI+)m/z 199[M+H]+。
中间体74
4-{4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-基}苯甲醛
根据用于中间体66的程序制备标题产物,使用2-(2-甲氧基乙氧基)乙基甲烷磺酸酯(中间体73)代替2-溴乙基乙基醚。
4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-甲酸叔丁酯:MS(ESI+)m/z289[M+H]+。
1-[2-(2-甲氧基乙氧基)乙基]哌嗪:MS(ESI+)m/z 189[M+H]+。
4-{4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=9.16Hz,2H)7.04(d,J=8.85Hz,2H)3.54(t,J=5.95Hz,2H)3.51(t,J=4.80Hz,2H)3.44(t,J=4.80Hz,2H)3.34-3.39(m,4H)3.25(s,3H)2.53-2.56(m,4H)2.52(t,J=5.95Hz,2H).MS(ESI+)m/z 293[M+H]+。
中间体75
4-(4-吡嗪-2-基哌嗪-1-基)苯甲醛
根据用于中间体56的程序制备标题产物,使用2-哌嗪-1-基吡嗪代替1-(2-甲氧基乙基)哌嗪。1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)8.36(d,J=1.2Hz,1H)8.11(dd,J=2.7,1.5Hz,1H)7.87(d,J=2.7Hz,1H)7.74(d,J=8.9Hz,2H)7.09(d,J=8.9Hz,2H)3.72-3.77(m,4H)3.55-3.59(m,4H).MS(ESI+)m/z 269[M+H]+。
中间体76
4-[4-(吡啶-2-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体56的程序制备标题产物,使用1-(吡啶-2-基甲基)哌嗪代替1-(2-甲氧基乙基)哌嗪。1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)8.51(ddd,J=4.9,1.8,0.9Hz,1H)7.78(td,J=7.6,1.8Hz,1H)7.70(d,J=8.9Hz,2H)7.48(d,J=7.9Hz,1H)7.28(ddd,J=7.3,4.9,1.2Hz,1H)7.04(d,J=8.9Hz,2H)3.65(s,2H)3.40(t,J=5.2Hz,4H)2.55(t,J=5.2Hz,4H).MS(ESI+)m/z 282[M+H]+。
中间体77
4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体56的程序制备标题产物,使用1-(吡啶-3-基甲基)哌嗪代替1-(2-甲氧基乙基)哌嗪。粗制产物通过快速色谱(二氧化硅,1-3%MeOH/DCM)纯化。1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)8.53(d,J=1.5Hz,1H)8.49(dd,J=4.9,1.8Hz,1H)7.74(dt,J=7.7,1.9Hz,1H)7.70(d,J=8.9Hz,2H)7.38(ddd,J=7.6,4.9,0.6Hz,1H)7.03(d,J=8.9Hz,2H)3.57(s,2H)3.39(t,J=4.9Hz,4H)2.50(t,J=4.9Hz,4H).MS(ESI+)m/z282[M+H]+。
中间体78
4-[4-(吡啶-4-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体56的程序制备标题产物,使用1-(吡啶-4-基甲基)哌嗪代替1-(2-甲氧基乙基)哌嗪。粗制产物通过快速色谱(二氧化硅,3%MeOH/DCM)纯化。1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)8.51-8.54(m,2H)7.71(d,J=8.9Hz,2H)7.36(d,J=5.8Hz,2H)7.04(d,J=8.9Hz,2H)3.57(s,2H)3.41(t,J=5.2Hz,4H)2.51(t,J=5.2Hz,4H).MS(ESI+)m/z 282[M+H]+。
中间体79
4-(4-吡啶-3-基哌嗪-1-基)苯甲醛
根据用于中间体56的程序制备标题产物,使用1-吡啶-3-基哌嗪代替1-(2-甲氧基乙基)哌嗪.通过用MeOH研磨两次纯化粗制产物。1H NMR(600MHz,DMSO-d6)δppm 9.74(s,1H)8.36(d,J=3.1Hz,1H)8.03(dd,J=4.3,1.2Hz,1H)7.74(d,J=9.2Hz,2H)7.38(ddd,J=8.5,3.1,1.2Hz,1H)7.24(dd,J=8.5,4.6Hz,1H)7.12(d,J=9.2Hz,2H)3.57(t,J=5.2Hz,4H)3.36(t,J=5.5Hz,4H).MS(ESI+)m/z 268[M+H]+。
中间体80
4-{4-[(6-甲基吡啶-2-基)甲基]哌嗪-1-基}苯甲醛
向N-boc-哌嗪(931mg,5.0mmol)和6-甲基-2-吡啶甲醛(606mg,5.0mmol)在DCE(30mL)中的搅拌的混合物中添加NaBH(OAc)3(1.696g,8.0mmol)。将混合物在室温下搅拌16小时。添加饱和NaHCO3(10mL),并将混合物搅拌10分钟。将混合物用DCM(25mL)稀释,分离各相。有机相用饱和NaHCO3(5mL)和盐水(5mL)洗涤,经Na2SO4干燥,并真空浓缩,产生1.44g(98%)基本上纯的4-[(6-甲基吡啶-2-基)甲基]哌嗪-1-甲酸叔丁酯,为澄清的几乎无色油状物。1H NMR(600MHz,DMSO-d6)δppm 7.64(t,J=7.6Hz,1H)7.22(d,J=7.6Hz,1H)7.11(d,J=7.6Hz,1H)3.54(s,2H)3.32(t,J=5.2Hz,4H)2.43(s,3H)2.35(t,J=5.2Hz,4H)1.39(s,9H).MS(ESI+)m/z 292[M+H]+。
向4-[(6-甲基吡啶-2-基)甲基]哌嗪-1-甲酸叔丁酯(1.44g,4.92mmol)在二噁烷(20mL)中的溶液中添加浓HCl(2mL,25mmol),并将混合物在室温下搅拌1.5小时。将混合物蒸发至小体积,添加水(12mL),产生的水相用EtOAc(15mL)洗涤。分离各相,用8M NaOH将水相的pH调节至约pH12,然后用DCM(3×25mL)萃取。将合并的有机相用盐水(5mL)洗涤,经Na2SO4干燥,最后蒸发,产生899mg(95%)纯的1-[(6-甲基吡啶-2-基)甲基]哌嗪,为澄清的几乎无色油状物。1H NMR(600MHz,DMSO-d6)δppm 7.62(t,J=7.6Hz,1H)7.21(d,J=7.6Hz,1H)7.09(d,J=7.6Hz,1H)3.48(s,2H)2.68(t,J=4.7Hz,4H)2.42(s,3H)2.32(br.s.,4H).MS(ESI+)m/z 192[M+H]+。
向p-氟苯甲醛(712mg,5.74mmol)和1-[(6-甲基吡啶-2-基)甲基]哌嗪(897mg,4.69mmol)的搅拌的混合物中添加溶解在水(12mL)中的碳酸钾(1.30g,9.38mmol),将混合物在密封管中在100℃下搅拌24小时。让反应混合物冷却至室温,添加DCM(35mL),分离各相。水相用DCM(25mL)萃取,合并的有机相经Na2SO4干燥并蒸发,产生1.44g 94%纯度的粗制物质,为浅棕色油状物。粗制产物通过快速色谱(二氧化硅,2-4%MeOH/DCM)纯化。合并纯的级分并蒸发,产生1.06g(76%)的>99%纯度标题产物,为澄清的微黄色油状物。1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=8.9Hz,2H)7.66(t,J=7.6Hz,1H)7.27(d,J=7.6Hz,1H)7.13(d,J=7.3Hz,1H)7.04(d,J=8.9Hz,2H)3.60(s,2H)3.40(t,J=5.2Hz,4H)2.55(t,J=4.9Hz,4H)2.45(s,3H).MS(ESI+)m/z 296[M+H]+。
中间体81
4-[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用2-噻唑甲醛代替6-甲基-2-吡啶甲醛。
4-(1,3-噻唑-2-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 7.72(d,J=3.4Hz,1H)7.66(d,J=3.4Hz,1H)3.85(s,2H)3.33(br.s.,4H)2.44(t,J=5.2Hz,4H)1.39(s,9H).MS(ESI+)m/z 284[M+H]+。
1-(1,3-噻唑-2-基甲基)哌嗪:1H NMR(600MHz,DMSO-d6)δppm 7.70(d,J=3.4Hz,1H)7.64(d,J=3.1Hz,1H)3.77(s,2H)2.70(br.s.,4H)2.40(br.s.,4H).MS(ESI+)m/z 184[M+H]+。
4-[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.72(s,1H)7.74(d,J=3.4Hz,1H)7.71(d,J=9.2Hz,2H)7.68(d,J=3.4Hz,1H)7.05(d,J=8.9Hz,2H)3.91(s,2H)3.42(t,J=5.2Hz,4H)2.63(t,J=5.2Hz,4H).MS(ESI+)m/z 288[M+H]+。
中间体82
4-[4-(1H-咪唑-4-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用1H-咪唑-4-甲醛代替6-甲基-2-吡啶甲醛。
4-(1H-咪唑-4-基甲基)哌嗪-1-甲酸叔丁酯:MS(ESI+)m/z 267[M+H]+。
1-(1H-咪唑-4-基甲基)哌嗪:产物没有分离。碱性的水相直接用于下一步骤。MS(ESI+)m/z 167[M+H]+。
4-[4-(1H-咪唑-4-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm11.93(br.s.,1H)9.70(s,1H)7.69(d,J=9.2Hz,2H)7.55(d,J=1.2Hz,1H)7.03(d,J=8.9Hz,2H)6.90(br.s.,1H)3.45(s,2H)3.37(t,J=5.2Hz,4H)2.50(t,J=5.2Hz,4H).MS(ESI+)m/z 271[M+H]+。
中间体83
4-{4-[(3,5-二甲基异噁唑-4-基)甲基]哌嗪-1-基}苯甲醛
根据用于中间体80的程序制备标题产物,使用3,5-二甲基-4-异噁唑甲醛代替6-甲基-2-吡啶甲醛。
4-[(3,5-二甲基异噁唑-4-基)甲基]哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 3.28(br.s.,4H)3.23(s,2H)2.31(s,3H)2.26(t,J=4.9Hz,4H)2.16(s,3H)1.38(s,9H).MS(ESI+)m/z 296[M+H]+。
1-[(3,5-二甲基异噁唑-4-基)甲基]哌嗪:1H NMR(600MHz,DMSO-d6)δppm 3.17(s,2H)2.64(t,J=4.4Hz,4H)2.30(s,3H)2.22(br.s.,4H)2.16(s,3H).MS(ESI+)m/z 196[M+H]+。
4-{4-[(3,5-二甲基异噁唑-4-基)甲基]哌嗪-1-基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=8.9Hz,2H)7.03(d,J=8.9Hz,2H)3.37(t,J=5.2Hz,4H)3.29(s,2H)2.45(t,J=4.9Hz,4H)2.34(s,3H)2.19(s,3H).MS(ESI+)m/z 300[M+H]+。
中间体84
4-[4-(呋喃-2-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用2-糠醛代替6-甲基-2-吡啶甲醛。
4-(呋喃-2-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 7.58(d,J=1.8Hz,1H)6.39(dd,J=3.1,1.8Hz,1H)6.28(d,J=3.1Hz,1H)3.50(s,2H)3.29(br.s.,4H)2.31(t,J=5.2Hz,4H)1.38(s,9H).MS(ESI+)m/z 267[M+H]+。
1-(呋喃-2-基甲基)哌嗪:1H NMR(600MHz,CD3OD)δppm 7.46(dd,J=1.8,0.6Hz,1H)6.37(dd,J=3.2,2.0Hz,1H)6.30(dd,J=3.1,0.6Hz,1H)3.55(s,2H)2.84(t,J=5.0Hz,4H)2.48(br.s.,4H).MS(ESI+)m/z 167[M+H]+。
4-[4-(呋喃-2-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=8.9Hz,2H)7.60(dd,J=1.8,0.9Hz,1H)7.03(d,J=8.9Hz,2H)6.41(dd,J=3.1,1.8Hz,1H)6.32(d,J=3.4Hz,1H)3.55(s,2H)3.38(t,J=5.2Hz,4H)2.50(t,J=5.2Hz,4H).MS(ESI+)m/z 271[M+H]+。
中间体85
4-{[4-(嘧啶-5-基甲基)哌嗪-1-基]甲基}苯甲醛
根据用于中间体80的程序制备标题产物,使用嘧啶-5-甲醛代替6-甲基-2-吡啶甲醛。
4-(嘧啶-5-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 9.09(s,1H)8.73(s,2H)3.54(s,2H)3.31(br.s.,4H)2.33(t,J=5.2Hz,4H)1.38(s,9H).MS(ESI+)m/z 279[M+H]+。
5-(哌嗪-1-基甲基)嘧啶:产物没有分离。碱性的水相直接用于下一步骤。MS(ESI+)m/z 179[M+H]+。
4-{[4-(嘧啶-5-基甲基)哌嗪-1-基]甲基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.71(s,1H)9.11(s,1H)8.77(s,2H)7.70(d,J=8.9Hz,2H)7.04(d,J=8.9Hz,2H)3.60(s,2H)3.40(t,J=4.9Hz,4H)2.52(t,J=4.9Hz,4H).MS(ESI+)m/z 283[M+H]+。
中间体86
4-{4-[(6-甲基吡啶-3-基)甲基]哌嗪-1-基}苯甲醛
根据用于中间体80的程序制备标题产物,使用6-甲基烟醛代替6-甲基-2-吡啶甲醛。
4-[(6-甲基吡啶-3-基)甲基]哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm8.33(d,J=2.1Hz,1H)7.57(dd,J=7.8,2.3Hz,1H)7.20(d,J=7.9Hz,1H)3.45(s,2H)3.29(br.s.,4H)2.44(s,3H)2.29(t,J=5.2Hz,4H)1.38(s,9H).MS(ESI+)m/z 292[M+H]+。
1-[(6-甲基吡啶-3-基)甲基]哌嗪:1H NMR(600MHz,DMSO-d6)δppm 8.31(d,J=1.8Hz,1H)7.56(dd,J=7.8,2.3Hz,1H)7.19(d,J=7.9Hz,1H)3.39(s,2H)2.65(t,J=4.9Hz,4H)2.43(s,3H)2.25(br.s.,4H).MS(ESI+)m/z 192[M+H]+。
4-{4-[(6-甲基吡啶-3-基)甲基]哌嗪-1-基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)8.37(d,J=2.1Hz,1H)7.70(d,J=8.9Hz,2H)7.62(dd,J=7.9,2.4Hz,1H)7.22(d,J=7.9Hz,1H)7.03(d,J=8.9Hz,2H)3.51(s,2H)3.38(t,J=5.2Hz,4H)2.48(t,J=4.9Hz,4H)2.45(s,3H).MS(ESI+)m/z 296[M+H]+。
中间体87
4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用吡嗪-2-甲醛代替6-甲基-2-吡啶甲醛。
4-(吡嗪-2-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 8.68(d,J=1.5Hz,1H)8.58(dd,J=2.4,1.5Hz,1H)8.54(d,J=2.4Hz,1H)3.67(s,2H)3.32(br.s.,4H)2.39(t,J=4.9Hz,4H)1.39(s,9H).MS(ESI+)m/z 279[M+H]+。
2-(哌嗪-1-基甲基)吡嗪:1H NMR(600MHz,DMSO-d6)δppm 8.66(d,J=1.2Hz,1H)8.57(dd,J=2.4,1.5Hz,1H)8.52(d,J=2.4Hz,1H)3.61(s,2H)2.69(t,J=4.9Hz,4H)2.34(br.s.,4H).MS(ESI+)m/z 179[M+H]+。
4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)8.73(d,J=1.5Hz,1H)8.60(dd,J=2.4,1.5Hz,1H)8.56(d,J=2.4Hz,1H)7.70(d,J=9.2Hz,2H)7.04(d,J=8.9Hz,2H)3.73(s,2H)3.41(t,J=5.2Hz,4H)2.58(t,J=4.9Hz,4H).MS(ESI+)m/z 283[M+H]+。
中间体88
4-[4-(呋喃-2-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用呋喃-2-甲醛代替6-甲基-2-吡啶甲醛。
4-(呋喃-2-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 7.58(dd,J=1.8,0.6Hz,1H)6.39(dd,J=3.1,1.8Hz,1H)6.28(d,J=3.4Hz,1H)3.50(s,2H)3.29(br.s.,4H)2.31(t,J=5.2Hz,4H)1.38(s,9H).MS(ESI+)m/z 267[M+H]+。
1-(呋喃-2-基甲基)哌嗪:1H NMR(600MHz,DMSO-d6)δppm 7.57(d,J=0.9Hz,1H)6.38(dd,J=2.9,2.0Hz,1H)6.25(d,J=3.1Hz,1H)3.43(s,2H)2.67(t,J=4.7Hz,4H)2.29(br.s.,4H).MS(ESI+)m/z167[M+H]+。
4-[4-(呋喃-2-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.70(s,1H)7.69(d,J=8.9Hz,2H)7.60(dd,J=1.8,0.9Hz,1H)7.03(d,J=8.9Hz,2H)6.41(dd,J=3.1,2.1Hz,1H)6.31(d,J=3.1Hz,1H)3.55(s,2H)3.38(t,J=5.2Hz,4H)2.50(t,J=5.2Hz,4H).MS(ESI+)m/z 271[M+H]+。
中间体89
4-{4-[(5-甲基呋喃-2-基)甲基]哌嗪-1-基}苯甲醛
根据用于中间体80的程序制备标题产物,使用5-甲基呋喃-2-甲醛代替6-甲基-2-吡啶甲醛。
4-[(5-甲基呋喃-2-基)甲基]哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm6.13(d,J=3.1Hz,1H)5.98(dd,J=2.9,1.1Hz,1H)3.41(s,2H)3.29(br.s.,4H)2.30(t,J=5.2Hz,4H)2.22(s,3H)1.38(s,9H).MS(ESI+)m/z 281[M+H]+。
1-[(5-甲基呋喃-2-基)甲基]哌嗪:1H NMR(600MHz,DMSO-d6)δppm 6.10(d,J=3.1Hz,1H)5.96(dd,J=3.0,1.1Hz,1H)3.34(s,2H)2.66(t,J=4.9Hz,4H)2.28(br.s.,4H)2.22(s,3H).MS(ESI+)m/z 181[M+H]+。
4-{4-[(5-甲基呋喃-2-基)甲基]哌嗪-1-基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=9.2Hz,2H)7.03(d,J=9.2Hz,2H)6.16(d,J=3.1Hz,1H)5.99(dd,J=2.7,0.9Hz,1H)3.47(s,2H)3.38(t,J=5.2Hz,4H)2.50(t,J=5.2Hz,4H)2.23(s,3H).MS(ESI+)m/z 285[M+H]+。
中间体90
4-[4-(呋喃-3-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用呋喃-3-甲醛代替6-甲基-2-吡啶甲醛。
4-(呋喃-3-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 7.60(t,J=1.5Hz,1H)7.54-7.55(m,1H)6.41(dd,J=1.8,0.9Hz,1H)3.32(s,2H)3.29(br.s.,4H)2.28(t,J=5.2Hz,4H)1.38(s,9H).MS(ESI+)m/z 267[M+H]+。
1-(呋喃-3-基甲基)哌嗪:1H NMR(600MHz,DMSO-d6)δppm 7.59(t,J=1.7Hz,1H)7.52(d,J=0.9Hz,1H)6.40(d,J=0.9Hz,1H)3.26(s,2H)2.67(t,J=4.9Hz,4H)2.26(br.s.,4H).MS(ESI+)m/z 167[M+H]+。
4-[4-(呋喃-3-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=8.9Hz,2H)7.62(t,J=1.5Hz,1H)7.59(s,1H)7.03(d,J=8.9Hz,2H)6.45(d,J=0.9Hz,1H)3.38(t,J=4.9Hz,4H)3.38(s,2H)2.48(t,J=4.9Hz,4H).MS(ESI+)m/z271[M+H]+。
中间体91
4-[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用噻唑-4-甲醛代替6-甲基-2-吡啶甲醛。
4-(1,3-噻唑-4-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 9.04(d,J=2.1Hz,1H)7.51(d,J=2.1Hz,1H)3.66(s,2H)3.30(t,J=4.9Hz,4H)2.37(t,J=4.9Hz,4H)1.38(s,9H).MS(ESI+)m/z 284[M+H]+。
1-(1,3-噻唑-4-基甲基)哌嗪:1H NMR(600MHz,DMSO-d6)δppm 9.02(d,J=2.1Hz,1H)7.47(d,J=2.1Hz,1H)3.59(s,2H)2.67(t,J=4.9Hz,4H)2.33(br.s.,4H).MS(ESI+)m/z184[M+H]+。
4-[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.71(s,1H)9.06(d,J=2.1Hz,1H)7.70(d,J=8.9Hz,2H)7.56(d,J=2.1Hz,1H)7.03(d,J=9.2Hz,2H)3.72(s,2H)3.39(t,J=5.2Hz,4H)2.56(t,J=5.2Hz,4H).MS(ESI+)m/z 288[M+H]+。
中间体92
4-[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用噻唑-5-甲醛代替6-甲基-2-吡啶甲醛。
4-(1,3-噻唑-5-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 9.03(s,1H)7.76(s,1H)3.76(s,2H)3.30(br.s.,4H)2.33(t,J=4.9Hz,4H)1.38(s,9H).MS(ESI+)m/z 284[M+H]+。
1-(1,3-噻唑-5-基甲基)哌嗪:1H NMR(600MHz,DMSO-d6)δppm 9.01(s,1H)7.74(s,1H)3.68(s,2H)2.66(t,J=4.9Hz,4H)2.29(br.s.,4H).MS(ESI+)m/z 184[M+H]+。
4-[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.71(s,1H)9.05(d,J=0.6Hz,1H)7.80(d,J=0.6Hz,1H)7.70(d,J=8.9Hz,2H)7.03(d,J=8.9Hz,2H)3.82(s,2H)3.39(t,J=5.2Hz,4H)2.52(t,J=5.2Hz,4H).MS(ESI+)m/z 288[M+H]+。
中间体93
4-{4-[(1-甲基-1H-咪唑-2-基)甲基]哌嗪-1-基}苯甲醛
根据用于中间体80的程序制备标题产物,使用1-甲基-1H-咪唑-2-甲醛代替6-甲基-2-吡啶甲醛。
4-[(1-甲基-1H-咪唑-2-基)甲基]哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 7.07(d,J=1.2Hz,1H)6.74(d,J=1.2Hz,1H)3.63(s,3H)3.51(s,2H)3.27(br.s.,4H)2.30(t,J=4.9Hz,4H)1.38(s,9H).MS(ESI+)m/z 281[M+H]+。
1-[(1-甲基-1H-咪唑-2-基)甲基]哌嗪:1H NMR(600MHz,DMSO-d6)δppm 7.06(d,J=1.2Hz,1H)6.73(d,J=1.2Hz,1H)3.63(s,3H)3.46(s,2H)2.67(t,J=4.9Hz,4H)2.27(br.s.,4H).MS(ESI+)m/z 181[M+H]+。
4-{4-[(1-甲基-1H-咪唑-2-基)甲基]哌嗪-1-基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=8.9Hz,2H)7.09(d,J=0.9Hz,1H)7.03(d,J=8.9Hz,2H)6.77(d,J=1.2Hz,1H)3.67(s,3H)3.57(s,2H)3.36(t,J=4.9Hz,4H)2.49(t,J=5.2Hz,4H).MS(ESI+)m/z 285[M+H]+。
中间体94
4-{4-[(5-甲基吡啶-2-基)甲基]哌嗪-1-基}苯甲醛
根据用于中间体80的程序制备标题产物,使用5-甲基吡啶-2-甲醛代替6-甲基-2-吡啶甲醛。
4-[(5-甲基吡啶-2-基)甲基]哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm8.32(d,J=2.4Hz,1H)7.57(dd,J=7.8,1.7Hz,1H)7.31(d,J=7.9Hz,1H)3.55(s,2H)3.30(br.s.,4H)2.34(t,J=4.9Hz,4H)2.27(s,3H)1.38(s,9H).MS(ESI+)m/z 292[M+H]+。
1-[(5-甲基吡啶-2-基)甲基]哌嗪:1H NMR(600MHz,DMSO-d6)δppm 8.30(dd,J=1.5,0.9Hz,1H)7.55(dd,J=7.9,1.8Hz,1H)7.30(d,J=7.9Hz,1H)3.48(s,2H)2.67(t,J=4.9Hz,4H)2.30(br.s.,4H)2.26(s,3H).MS(ESI+)m/z 192[M+H]+。
4-{4-[(5-甲基吡啶-2-基)甲基]哌嗪-1-基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)8.34(d,J=1.8Hz,1H)7.70(d,J=8.9Hz,2H)7.59(dd,J=7.9,1.8Hz,1H)7.36(d,J=7.9Hz,1H)7.03(d,J=9.2Hz,2H)3.60(s,2H)3.39(t,J=5.2Hz,4H)2.53(t,J=5.2Hz,4H)2.28(s,3H).MS(ESI+)m/z 296[M+H]+。
中间体95
4-[4-(2-甲氧基乙基)-3-甲基哌嗪-1-基]苯甲醛
根据用于中间体66的程序制备标题产物,使用N-1-boc-3-甲基哌嗪代替1-boc-哌嗪,用2-溴乙基甲基醚代替2-溴乙基乙基醚。
4-(2-甲氧基乙基)-3-甲基哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm3.67-3.75(m,1H)3.64-3.71(m,1H)3.54(ddd,J=10.22,6.80,4.81Hz,1H)3.50(ddd,J=10.22,5.95,5.19Hz,1H)3.33(s,3H)3.09-3.18(m,1H)2.89-2.96(m,1H)2.87(ddd,J=11.98,4.12,3.43Hz,1H)2.72-2.91(m,1H)2.51(ddd,J=13.77,5.95,4.81Hz,1H)2.41-2.48(m,1H)2.28-2.36(m,1H)1.45(s,9H)1.06(d,J=6.10Hz,3H).MS(ESI+)m/z 259[M+H]+。
1-(2-甲氧基乙基)-2-甲基哌嗪:1H NMR(600MHz,CD3OD)δppm 3.54(ddd,J=10.18,6.81,4.94Hz,1H)3.51(ddd,J=10.18,5.93,5.27Hz,1H)3.33(s,3H)2.97(ddd,J=13.77,6.83,5.34Hz,1H)2.88-2.93(m,2H)2.85(ddd,J=12.32,2.78,1.53Hz,1H)2.77-2.83(m,1H)2.45-2.52(m,2H)2.38-2.45(m,1H)2.36(ddd,J=12.05,11.14,3.36Hz,1H)1.05(d,J=6.26Hz,3H).MS(ESI+)m/z 159[M+H]+。
4-[4-(2-甲氧基乙基)-3-甲基哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.70(s,1H)7.67-7.71(m,2H)7.01-7.06(m,2H)3.67-3.73(m,2H)3.40-3.47(m,2H)3.24(s,3H)3.03(ddd,J=12.50,10.40,3.20Hz,1H)2.92(ddd,J=11.80,3.60,3.20Hz,1H)2.86(dt,J=13.54,6.20Hz,1H)2.73(dd,J=12.51,9.16Hz,1H)2.45-2.50(m,1H)2.42(dt,J=13.54,5.82Hz,1H)2.38(ddd,J=11.80,10.40,3.14Hz,1H)1.05(d,J=6.26Hz,3H).MS(ESI+)m/z 263[M+H]+。
中间体96
4-[3-甲基-4-(吡啶-3-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用3-吡啶甲醛代替6-甲基-2-吡啶甲醛,用N-1-boc-3-甲基哌嗪代替1-boc-哌嗪。
3-甲基-4-(吡啶-3-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm8.50(ddt,J=2.19,0.89,0.65Hz,1H)8.43(dd,J=4.84,1.66Hz,1H)7.85(dddt,J=7.84,2.19,1.66,0.54,Hz,1H)7.42(ddd,J=7.84,4.91,0.89Hz,1H)4.03(d,J=13.73Hz,1H)3.66-3.74(m,1H)3.57-3.68(m,1H)3.34(d,J=13.73Hz,1H)3.13(ddd,J=12.89,9.61,2.98Hz,1H)2.76-3.08(m,1H)2.60-2.68(m,1H)2.44-2.52(m,1H)2.10-2.18(m,1H)1.45(s,9H)1.16(d,J=6.26Hz,3H).MS(ESI+)m/z 292[M+H]+。
2-甲基-1-(吡啶-3-基甲基)哌嗪:1H NMR(600MHz,CD3OD)δppm 8.50(ddt,J=2.20,0.91,0.60Hz,1H)8.43(dd,J=4.89,1.66Hz,1H)7.84(dddt,J=7.82,2.20,1.66,0.51Hz,1H)7.42(ddd,J=7.82,4.89,0.91Hz,1H)4.12(d,J=13.73Hz,1H)3.28(d,J=13.73Hz,1H)2.92(ddd,J=12.52,2.95,1.37Hz,1H)2.87(dtd,J=12.57,3.10,1.30Hz,1H)2.75(ddd,J=12.60,10.89,3.10Hz,1H)2.65(dt,J=11.91,3.10Hz,1H)2.55(dd,J=12.52,9.72Hz,1H)2.44(dqd,J=9.72,6.24,2.95Hz,1H)2.16(ddd,J=11.89,10.89,3.10Hz,1H)1.18(d,J=6.24Hz,3H).MS(ESI+)m/z 192[M+H]+。
4-[3-甲基-4-(吡啶-3-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.70(s,1H)8.53(d,J=2.00Hz,1H)8.47(dd,J=4.81,1.68Hz,1H)7.74(ddd,J=7.77,2.00,1.68Hz,1H)7.67-7.71(m,2H)7.37(ddd,J=7.77,4.81,0.61Hz,1H)7.01-7.05(m,2H)4.01(d,J=13.73Hz,1H)3.76(ddd,J=12.55,3.09,1.59Hz,1H)3.63-3.69(m,1H)3.27(d,J=13.73Hz,1H)3.02(ddd,J=12.55,10.16,3.09Hz,1H)2.85(dd,J=12.55,8.97Hz,1H)2.69(ddd,J=11.76,3.90,3.09Hz,1H)2.53(dqd,J=8.97,6.22,3.09Hz,1H)2.21(ddd,J=11.67,10.16,3.09Hz,1H)1.17(d,J=6.22Hz,3H).MS(ESI+)m/z 296[M+H]+。
中间体97
4-[4-(3-甲氧基丙基)-3-甲基哌嗪-1-基]苯甲醛
根据用于中间体66的程序制备标题产物,使用N-1-boc-3-甲基哌嗪代替1-boc-哌嗪,用3-溴丙基甲基醚代替2-溴乙基乙基醚。
4-(3-甲氧基丙基)-3-甲基哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm3.68-3.78(m,1H)3.65-3.71(m,1H)3.42(t,J=6.18Hz,2H)3.32(s,3H)3.08-3.18(m,1H)2.77-2.84(m,2H)2.70-2.96(m,1H)2.35-2.45(m,2H)2.20-2.30(m,1H)1.65-1.81(m,2H)1.45(s,9H)1.05(d,J=6.26Hz,3H).MS(ESI+)m/z 273[M+H]+。
1-(3-甲氧基丙基)-2-甲基哌嗪:1H NMR(600MHz,CD3OD)δppm 3.42(t,J=6.18Hz,2H)3.32(s,3H)2.90(dtd,J=12.40,3.09,1.53Hz,1H)2.81-2.87(m,J=14.10,1.83,1.50,1.50Hz,3H)2.79(ddd,J=12.51,11.00,2.95Hz,1H)2.45(dd,J=12.47,9.78Hz,1H)2.39(ddd,J=12.98,10.42,5.04Hz,1H)2.33-2.39(m,1H)2.27(ddd,J=11.62,11.00,3.09Hz,1H)1.74-1.82(m,1H)1.66-1.74(m,1H)1.05(d,J=6.26Hz,3H).MS(ESI+)m/z 173[M+H]+。
4-[4-(3-甲氧基丙基)-3-甲基哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.70(s,1H)7.67-7.71(m,2H)7.01-7.06(m,2H)3.67-3.74(m,2H)3.35(t,J=6.33Hz,2H)3.22(s,3H)3.03(ddd,J=12.36,10.38,3.20Hz,1H)2.87(dt,J=11.60,3.43Hz,1H)2.70-2.78(m,2H)2.40-2.46(m,1H)2.21-2.29(m,2H)1.57-1.71(m,2H)1.04(d,J=6.26Hz,3H).MS(ESI+)m/z 277[M+H]+。
中间体98
4-[3-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用2-噻唑甲醛代替6-甲基-2-吡啶甲醛,用N-1-boc-3-甲基哌嗪代替1-boc-哌嗪。
3-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm7.71(d,J=3.36Hz,1H)7.53(d,J=3.36Hz,1H)4.17(d,J=15.56Hz,1H)3.84(d,J=15.56Hz,1H)3.67-3.73(m,1H)3.62-3.71(m,1H)3.20(ddd,J=12.55,9.73,2.75Hz,1H)2.78-3.04(m,1H)2.80(dt,J=11.50,3.81Hz,1H)2.54-2.62(m,1H)2.37(ddd,J=11.44,9.70,3.36Hz,1H)1.45(s,9H)1.13(d,J=6.41Hz,3H).MS(ESI+)m/z 298[M+H]+。
2-甲基-1-(1,3-噻唑-2-基甲基)哌嗪:1H NMR(600MHz,CD3OD)δppm 7.71(d,J=3.36Hz,1H)7.53(d,J=3.36Hz,1H)4.20(d,J=15.50Hz,1H)3.81(d,J=15.50Hz,1H)2.86-2.92(m,2H)2.77-2.84(m,2H)2.48-2.56(m,2H)2.37-2.43(m,1H)1.13(d,J=5.95Hz,3H).MS(ESI+)m/z 198[M+H]+。
4-[3-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.70(s,1H)7.74(d,J=3.30Hz,1H)7.68-7.71(m,2H)7.65(d,J=3.30Hz,1H)7.02-7.06(m,2H)4.18(d,J=15.48Hz,1H)3.85(d,J=15.48Hz,1H)3.77(ddd,J=12.63,3.10,1.70Hz,1H)3.70-3.75(m,1H)3.07(ddd,J=12.66,10.07,3.05Hz,1H)2.88(dt,J=11.71,3.45Hz,1H)2.83(dd,J=12.63,9.10Hz,1H)2.64(dqd,J=9.10,6.26,3.10Hz,1H)2.46(ddd,J=11.71,10.30,3.13Hz,1H)1.15(d,J=6.26Hz,3H).MS(ESI+)m/z 302[M+H]+。
中间体99
4-[2-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯甲醛
根据用于中间体80的程序制备标题产物,使用2-噻唑甲醛代替6-甲基-2-吡啶甲醛,用N-1-boc-2-甲基哌嗪代替1-boc-哌嗪。最后一步在100℃搅拌5天。
2-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm7.70(d,J=3.36Hz,1H)7.55(d,J=3.36Hz,1H)4.19-4.25(m,1H)3.89(d,J=15.11Hz,1H)3.83(dddd,J=13.27,3.48,1.98,0.97Hz,1H)3.80(d,J=15.11Hz,1H)3.16(ddd,J=13.27,12.25,3.27Hz,1H)2.87-2.92(m,1H)2.74(dt,J=11.24,1.90Hz,1H)2.32(dd,J=11.24,3.88Hz,1H)2.19(ddd,J=12.25,11.24,3.48Hz,1H)1.46(s,9H)1.29(d,J=6.71Hz,3H).MS(ESI+)m/z 298[M+H]+。
3-甲基-1-(1,3-噻唑-2-基甲基)哌嗪:1H NMR(600MHz,CD3OD)δppm 7.71(d,J=3.36Hz,1H)7.55(d,J=3.36Hz,1H)3.83-3.90(m,2H)2.91-2.96(m,1H)2.80-2.89(m,4H)2.17-2.25(m,1H)1.89(t,J=11.06Hz,1H)1.04(d,J=6.41Hz,3H).MS(ESI+)m/z 198[M+H]+。
4-[2-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯甲醛.1H NMR(600MHz,CD3OD)δppm 9.66(s,1H)7.73-7.77(m,2H)7.72(d,J=3.36Hz,1H)7.57(d,J=3.36Hz,1H)6.98-7.02(m,2H)4.28-4.34(m,1H)3.96(d,J=14.95Hz,1H)3.87(d,J=14.95Hz,1H)3.69-3.74(m,1H)3.27(ddd,J=12.52,11.93,3.56Hz,1H)3.05-3.10(m,1H)2.90(dt,J=11.20,2.19Hz,1H)2.53(dd,J=11.20,3.59Hz,1H)2.41(ddd,J=11.93,11.11,3.51Hz,1H)1.28(d,J=6.71Hz,3H).MS(ESI+)m/z 302[M+H]+。
中间体100
4-[4-(2-甲氧基乙基)-2-甲基哌嗪-1-基]苯甲醛
根据用于中间体66的程序制备标题产物,使用N-1-boc-2-甲基哌嗪代替1-boc-哌嗪,用2-溴乙基甲基醚代替2-溴乙基乙基醚。最后一步在100℃搅拌7天。
4-(2-甲氧基乙基)-2-甲基哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm4.13-4.20(m,1H)3.77(dddd,J=13.15,3.51,2.01,1.04Hz,1H)3.49-3.56(m,2H)3.34(s,3H)3.09(ddd,J=13.15,12.32,3.37Hz,1H)2.85(dddd,J=11.40,3.37,2.01,1.75Hz,1H)2.77(ddd,J=11.40,1.87,1.75Hz,1H)2.55(ddd,J=13.28,6.10,5.34Hz,1H)2.49(ddd,J=13.28,5.80,5.19Hz,1H)2.15(dd,J=11.40,4.04Hz,1H)1.99(ddd,J=12.32,11.40,3.51Hz,1H)1.45(s,9H)1.24(d,J=6.87Hz,3H).MS(ESI+)m/z 259[M+H]+。
1-(2-甲氧基乙基)-3-甲基哌嗪:1H NMR(600MHz,CD3OD)δppm 3.53(t,J=5.57Hz,2H)3.33(s,3H)2.89-2.93(m,1H)2.80-2.88(m,4H)2.56(t,J=5.57Hz,2H)2.04-2.10(m,1H)1.75(dd,J=11.50,10.30Hz,1H)1.04(d,J=6.41Hz,3H).MS(ESI+)m/z 159[M+H]+。
4-[4-(2-甲氧基乙基)-2-甲基哌嗪-1-基]苯甲醛:1H NMR(600MHz,CD3OD)δppm9.66(s,1H)7.72-7.76(m,2H)6.96-7.00(m,2H)4.23-4.30(m,1H)3.66(dddd,J=12.32,3.52,2.20,0.83Hz,1H)3.59(ddd,J=10.31,6.28,5.08Hz,1H)3.57(ddd,J=10.31,5.87,5.08Hz,1H)3.37(s,3H)3.20(td,J=12.32,3.52Hz,1H)3.03(ddt,J=11.29,3.52,2.20Hz,1H)2.93(dt,J=11.29,2.20Hz,1H)2.62(ddd,J=13.15,6.28,5.08Hz,1H)2.55(ddd,J=13.15,5.87,5.08Hz,1H)2.37(dd,J=11.29,3.81Hz,1H)2.22(ddd,J=12.32,11.29,3.62Hz,1H)1.23(d,J=6.71Hz,3H).MS(ESI+)m/z 263[M+H]+。
中间体101
4-(4-苄基哌嗪-1-基)苯甲醛
根据用于中间体80的程序制备标题产物,使用苯甲醛代替6-甲基-2-吡啶甲醛。
4-苄基哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 7.29-7.35(m,4H)7.24-7.28(m,1H)3.53(s,2H)3.39-3.46(m,4H)2.37-2.42(m,4H)1.45(s,9H).MS(ESI+)m/z 277[M+H]+。
1-苄基哌嗪:1H NMR(600MHz,CD3OD)δppm 7.29-7.34(m,4H)7.24-7.28(m,1H)3.51(s,2H)2.84(t,J=4.96Hz,4H)2.32-2.60(m,4H).MS(ESI+)m/z 177[M+H]+。
4-(4-苄基哌嗪-1-基)苯甲醛:1H NMR(600MHz,CD3OD)δppm 9.68(s,1H)7.72-7.76(m,2H)7.35-7.39(m,2H)7.31-7.36(m,2H)7.25-7.30(m,1H)7.00-7.04(m,2H)3.58(s,2H)3.41-3.46(m,4H)2.58-2.63(m,4H).MS(ESI+)m/z 281[M+H]+。
中间体102
4-[4-(3-甲氧基丙基)-2-甲基哌嗪-1-基]苯甲醛
根据用于中间体66的程序制备标题产物,使用N-1-boc-2-甲基哌嗪代替1-boc-哌嗪,用3-溴丙基甲基醚代替2-溴乙基乙基醚。最后一步在100℃搅拌7天。
4-(3-甲氧基丙基)-2-甲基哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm4.15-4.21(m,1H)3.78(dddd,J=13.29,3.51,2.01,0.99Hz,1H)3.45(t,J=6.36Hz,2H)3.32(s,3H)3.08(ddd,J=13.29,12.25,3.32Hz,1H)2.82(dddd,J=11.34,3.32,2.01,1.68Hz,1H)2.74(ddd,J=11.40,1.90,1.68Hz,1H)2.41(ddd,J=12.36,8.29,6.63Hz,1H)2.33(ddd,J=12.36,8.24,6.36Hz,1H)2.07(dd,J=11.40,4.12Hz,1H)1.91(ddd,J=12.25,11.34,3.51Hz,1H)1.69-1.80(m,2H)1.45(s,9H)1.23(d,J=6.71Hz,3H).MS(ESI+)m/z 273[M+H]+。
1-(3-甲氧基丙基)-3-甲基哌嗪:1H NMR(600MHz,CD3OD)δppm 3.42(t,J=6.26Hz,2H)3.32(s,3H)2.90-2.95(m,1H)2.78-2.87(m,4H)2.39-2.45(m,2H)1.97-2.04(m,1H)1.74-1.81(m,2H)1.69(t,J=11.06Hz,1H)1.05(d,J=6.41Hz,3H).MS(ESI+)m/z 173[M+H]+。
4-[4-(3-甲氧基丙基)-2-甲基哌嗪-1-基]苯甲醛:1H NMR(600MHz,CD3OD)δppm9.66(s,1H)7.72-7.76(m,2H)6.96-7.00(m,2H)4.25-4.31(m,1H)3.67(dddd,J=12.62,3.59,2.24,0.90Hz,1H)3.49(dd,J=6.67,6.42Hz,2H)3.34(s,3H)3.19(ddd,J=12.62,12.06,3.55Hz,1H)2.99(ddt,J=11.23,3.55,2.24Hz,1H)2.89(dt,J=11.23,2.24Hz,1H)2.47(ddd,J=12.22,8.25,6.67Hz,1H)2.39(ddd,J=12.22,8.11,6.42Hz,1H)2.29(dd,J=11.23,3.89Hz,1H)2.14(ddd,J=12.06,11.23,3.59Hz,1H)1.74-1.85(m,2H)1.22(d,J=6.71Hz,3H).MS(ESI+)m/z 277[M+H]+。
中间体103
4-[4-(2-甲氧基乙基)-3-氧代哌嗪-1-基]苯甲醛
向4-boc-哌嗪酮(2.00g,10.0mmol)在DMF(25mL)中的搅拌的混合物中添加氢化钠(95%干物质,505mg,20.0mmol)。将混合物在室温下搅拌20分钟,然后缓慢添加1-溴-2-甲氧基乙烷(2.78g,20.0mmol)/DMF(5mL),将反应混合物在室温下搅拌2小时。添加冰水(15mL),用DCM(2×50mL)萃取混合物。将合并的萃取物用水(3×10mL)和盐水(10mL)洗涤,经MgSO4干燥并真空浓缩,产生2.85g澄清的几乎无色的油状物。通过快速色谱(二氧化硅,1-2%MeOH/DCM)纯化,产生2.46g(95%)的4-(2-甲氧基乙基)-3-氧代哌嗪-1-甲酸叔丁酯,为澄清无色油状物。1H NMR(600MHz,CD3OD)δppm 4.03(s,2H)3.63(br.s.,2H)3.60(dd,J=4.6,1.2Hz,1H)3.59(dd,J=4.6,0.6Hz,1H)3.56(dd,J=4.6,0.9Hz,1H)3.55(dd,J=4.6,1.2Hz,1H)3.49(t,J=5.5Hz,2H)3.34(s,3H)1.48(s,9H).MS(ESI+)m/z 259[M+H]+。
根据用于中间体66的程序制备标题产物,使用来自前一步骤的产物。
1-(2-甲氧基乙基)哌嗪-2-酮三(三氟乙酸盐):1H NMR(600MHz,CD3OD)δppm 3.85(s,2H)3.71-3.74(m,2H)3.65(t,J=5.2Hz,2H)3.59(d,J=5.2Hz,1H)3.58(dd,J=5.5,0.6Hz,1H)3.50-3.53(m,2H)3.35(s,3H).MS(ESI+)m/z 159[M+H]+。
4-[4-(2-甲氧基乙基)-3-氧代哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.73(s,1H)7.73(d,J=8.9Hz,2H)7.00(d,J=8.9Hz,2H)4.00(s,2H)3.66(t,J=5.9Hz,2H)3.54(td,J=5.2Hz,4H)3.48(t,J=5.5Hz,2H)3.25(s,3H).MS(ESI+)m/z 263[M+H]+。
中间体104
4-[4-(甲氧基乙酰基)哌嗪-1-基]苯甲醛
将甲氧基乙酰氯(1.09g,10mmol)在冰浴温度下滴加到boc-哌嗪(1.86g,10mmol)和DIPEA(2.59g,20mmol,3.48mL)在DCM(25mL)中的溶液中。将反应混合物在冰浴温度下搅拌50分钟,然后在室温下搅拌0.5小时。添加DCM(10mL)和水(10mL)。将有机相用水(10mL)、2M柠檬酸(2×10mL)和盐水(10mL)洗涤,经MgSO4干燥,过滤并蒸发,产生1.95g(75%)的4-(甲氧基乙酰基)-哌嗪-1-甲酸叔丁酯,为无色油状物。1H NMR(600MHz,CDCl3)δppm 4.11(s,2H)3.55-3.62(m,2H)3.42(s,3H)3.40-3.49(m,6H)1.47(s,9H).MS(ESI+)m/z 259[M+H]+。
根据用于中间体66的程序制备标题产物,使用来自前一步骤的产物。
1-(甲氧基乙酰基)哌嗪三氟乙酸盐:1H NMR(600MHz,CDCl3)δppm 4.20(s,2H)3.78-3.85(m,2H)3.72-3.79(m,2H)3.41(s,3H)3.20-3.29(m,4H).MS(ESI+)m/z 159[M+H]+。
4-[4-(甲氧基乙酰基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)7.71-7.75(m,2H)7.03-7.07(m,2H)4.13(s,2H)3.56-3.61(m,2H)3.52-3.57(m,2H)3.43-3.47(m,2H)3.40-3.45(m,2H)3.30(s,3H).MS(ESI+)m/z 263[M+H]+。
中间体105
4-[4-(3-甲氧基丙基)-3-氧代哌嗪-1-基]苯甲醛
根据用于中间体103的程序制备标题产物,使用1-溴-3-甲氧基丙烷代替1-溴-2-甲氧基乙烷。
4-(3-甲氧基丙基)-3-氧代哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 4.01(br.s.,2H)3.60-3.68(m,2H)3.46-3.51(m,2H)3.39-3.44(m,4H)3.31(s,3H)1.80-1.86(m,2H)1.48(s,9H).MS(ESI+)m/z 273[M+H]+。
1-(3-甲氧基丙基)哌嗪-2-酮三氟乙酸盐:1H NMR(600MHz,CD3OD)δppm 3.83(s,2H)3.61-3.65(m,2H)3.50-3.54(m,4H)3.44(t,J=5.95Hz,2H)3.33(s,3H)1.82-1.89(m,2H).MS(ESI+)m/z173[M+H]+。
4-[4-(3-甲氧基丙基)-3-氧代哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.73(s,1H)7.71-7.75(m,2H)6.98-7.02(m,2H)3.98(s,2H)3.64-3.69(m,2H)3.45-3.50(m,2H)3.37-3.43(m,2H)3.30-3.33(m,2H)3.21(s,3H)1.70-1.77(m,2H).MS(ESI+)m/z277[M+H]+。
中间体106
4-[4-(2-乙氧基乙基)-3-氧代哌嗪-1-基]苯甲醛
根据用于中间体103的程序制备标题产物,使用1-溴-2-乙氧基乙烷代替1-溴-2-甲氧基乙烷。
4-(2-乙氧基乙基)-3-氧代哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 4.03(s,2H)3.63(br.s.,2H)3.57-3.61(m,4H)3.49-3.52(m,2H)3.50(q,J=7.0Hz,2H)1.48(s,9H)1.17(t,J=7.0Hz,3H).MS(ESI+)m/z 273[M+H]+。
1-(2-乙氧基乙基)哌嗪-2-酮三氟乙酸盐:1H NMR(600MHz,CD3OD)δppm3.85(s,2H)3.74(dd,J=6.1,5.5Hz,2H)3.61-3.66(m,4H)3.50-3.53(m,2H)3.52(q,J=7.0Hz,2H)1.18(t,J=7.0Hz,3H).MS(ESI+)m/z 173[M+H]+。
4-[4-(2-乙氧基乙基)-3-氧代哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.73(s,1H)7.73(d,J=8.9Hz,2H)7.01(d,J=8.9Hz,2H)4.00(s,2H)3.66(dd,J=6.4,4.3Hz,2H)3.49-3.56(m,6H)3.42(q,J=7.0Hz,2H)1.08(t,J=6.9Hz,3H).MS(ESI+)m/z277[M+H]+。
中间体107
4-[4-(2-羟基乙基)哌啶-1-基]苯甲醛
根据用于中间体66的程序的最后一步制备标题产物,使用4-哌啶乙醇和4-氟苯甲醛。1H NMR(600MHz,CD3OD)δppm 9.67(s,1H)7.66-7.69(m,2H)6.99-7.03(m,2H)4.37(t,J=5.11Hz,1H)3.95-4.00(m,2H)3.46(td,J=6.61,5.11Hz,2H)2.87(td,J=12.70,2.52Hz,2H)1.70-1.76(m,2H)1.62-1.70(m,1H)1.37(q,J=6.61Hz,2H)1.11-1.20(m,J=12.70,12.11,12.11,4.04Hz,2H).MS(ESI+)m/z 234[M+H]+。
中间体108
4-[4-(3-羟基丙基)哌嗪-1-基]苯甲醛
根据用于中间体66的程序制备标题产物,使用3-溴-1-丙醇代替2-溴乙基乙基醚。
4-(3-羟基丙基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 4.42(br.s.,1H)3.42(t,J=6.33Hz,2H)3.24-3.31(m,4H)2.29-2.34(m,2H)2.24-2.30(m,4H)1.52-1.59(m,2H)1.39(s,9H).MS(ESI+)m/z 245[M+H]+。
3-哌嗪-1-基丙烷-1-醇:1H NMR(600MHz,CD3OD)δppm 3.61(t,J=6.26Hz,2H)2.84(t,J=4.96Hz,4H)2.44-2.48(m,2H)2.34-2.60(m,4H)1.70-1.77(m,2H).MS(ESI+)m/z 145[M+H]+。
4-[4-(3-羟基丙基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,CD3OD)δppm 9.71(s,1H)7.75-7.79(m,2H)7.03-7.07(m,2H)3.65(t,J=6.26Hz,2H)3.44-3.48(m,4H)2.62-2.67(m,4H)2.52-2.56(m,2H)1.76-1.82(m,2H).MS(ESI+)m/z 249[M+H]+。
中间体109
4-{4-[2-(1-甲基乙氧基)乙基]-3-氧代哌嗪-1-基}苯甲醛
根据用于中间体103的程序制备标题产物,使用2-(1-甲基乙氧基)乙基甲烷磺酸酯(中间体69)代替1-溴-2-甲氧基乙烷。
4-[2-(1-甲基乙氧基)乙基]-3-氧代哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 4.03(s,2H)3.62(br.s.,2H)3.59-3.61(m,2H)3.59(spt,J=6.1Hz,1H)3.54-3.57(m,2H)3.52(t,J=5.5Hz,2H)1.48(s,9H)1.13(d,J=6.1Hz,6H).MS(ESI+)m/z 287[M+H]+。
1-[2-(1-甲基乙氧基)乙基]哌嗪-2-酮三氟乙酸盐:1H NMR(600MHz,CD3OD)δppm3.85(s,2H)3.75(t,J=5.8Hz,2H)3.60-3.65(m,5H)3.51(t,J=5.8Hz,2H)1.15(d,J=6.1Hz,6H).MS(ESI+)m/z 187[M+H]+。
4-{4-[2-(1-甲基乙氧基)乙基]-3-氧代哌嗪-1-基}苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)7.73(d,J=8.9Hz,2H)7.01(d,J=8.9Hz,2H)4.00(s,2H)3.66(dd,J=6.4,4.3Hz,2H)3.56(dd,J=6.4,4.3Hz,2H)3.53(spt,J=6.1Hz,1H)3.50(s,4H)1.05(d,J=5.8Hz,6H).MS(ESI+)m/z 291[M+H]+。
中间体110
4-[4-(3-甲氧基丙酰基)哌嗪-1-基]苯甲醛
根据用于中间体104的程序制备标题产物,使用3-甲氧基丙酰氯代替甲氧基乙酰氯。
4-(3-甲氧基丙酰基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 3.66(t,J=6.23Hz,2H)3.53-3.60(m,4H)3.43-3.49(m,2H)3.37-3.44(m,2H)3.33(s,3H)2.66(t,J=6.23Hz,2H)1.47(s,9H).MS(ESI+)m/z 273[M+H]+。
1-(3-甲氧基丙酰基)哌嗪三氟乙酸盐:1H NMR(600MHz,CD3OD)δppm 3.80-3.85(m,4H)3.68(t,J=6.10Hz,2H)3.34(s,3H)3.22-3.27(m,2H)3.17-3.23(m,2H)2.69(t,J=6.03Hz,2H).MS(ESI+)m/z 173[M+H]+。
4-[4-(3-甲氧基丙酰基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)7.71-7.75(m,2H)7.02-7.06(m,2H)3.58-3.64(m,4H)3.57(t,J=6.56Hz,2H)3.43-3.48(m,2H)3.37-3.42(m,2H)3.23(s,3H)2.61(t,J=6.56Hz,2H).MS(ESI+)m/z 277[M+H]+。
中间体111
4-[4-(2-甲氧基乙基)哌啶-1-基]苯甲醛
将氢化钠(202mg,8.0mmol,95%)分多次添加到4-(2-羟基乙基)哌啶-1-甲酸叔丁酯(917mg,4.0mmol)在DMF(5mL)中的溶液中。将混合物在室温下搅拌0.5小时,缓慢添加甲基碘(1.14g,8.0mmol)/DMF(3mL)。18小时后,通过添加水(10mL)猝灭反应,并将产生的水相用EtOAc(3×20mL)萃取。将合并的有机相用盐水(2×5mL)洗涤,经MgSO4干燥,并真空浓缩,产生1.177g粗制物质,为浅黄色油状物。通过快速色谱(二氧化硅,10-20%EtOAc/正己烷)纯化,产生912mg(94%)纯的4-(2-甲氧基乙基)哌啶-1-甲酸叔丁酯,为无色油状物。1H NMR(600MHz,CD3OD)δppm 4.04(d,J=13.4Hz,2H)3.45(t,J=6.4Hz,2H)3.31(s,3H)2.73(br.s.,2H)1.69(d,J=12.5Hz,2H)1.54-1.64(m,1H)1.51(q,J=6.6Hz,2H)1.45(s,9H)1.07(qd,J=12.2,4.4Hz,2H).MS(ESI+)m/z 188[M+H-t-Bu]+。
根据用于中间体66的程序制备标题产物,使用前一步骤中所述的中间体。
4-(2-甲氧基乙基)哌啶盐酸盐:1H NMR(600MHz,CD3OD)δppm 3.46(t,J=6.3Hz,2H)3.37(d,J=12.8Hz,2H)3.32(s,3H)2.97(td,J=13.0,3.1Hz,2H)1.96(d,J=14.3Hz,2H)1.72-1.82(m,1H)1.57(q,J=6.4Hz,2H)1.40(qd,J=12.9,3.6Hz,2H).MS(ESI+)m/z144[M+H]+。
4-[4-(2-甲氧基乙基)哌啶-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.68(s,1H)7.67(d,J=8.9Hz,2H)7.01(d,J=8.9Hz,2H)3.98(d,J=13.4Hz,2H)3.37(t,J=6.6Hz,2H)3.22(s,3H)2.87(td,J=12.7,2.4Hz,2H)1.73(d,J=12.5Hz,2H)1.59-1.68(m,1H)1.45(q,J=6.6Hz,2H)1.16(qd,J=12.2,4.0Hz,2H).MS(ESI+)m/z 248[M+H]+。
中间体112
4-[4-(2-乙氧基乙基)哌啶-1-基]苯甲醛
根据用于中间体111的程序制备标题产物,使用乙基碘代替甲基碘。
4-(2-乙氧基乙基)哌啶-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 4.04(d,J=13.1Hz,2H)3.49(t,J=6.6Hz,2H)3.48(q,J=7.0Hz,2H)2.74(br.s.,2H)1.69(d,J=12.5Hz,2H)1.56-1.66(m,1H)1.51(q,J=6.6Hz,2H)1.45(s,9H)1.17(t,J=7.0Hz,3H)1.08(qd,J=12.2,4.4Hz,2H).MS(ESI+)m/z 202[M+H-t-Bu]+。
4-(2-乙氧基乙基)哌啶盐酸盐:1H NMR(600MHz,CD3OD)δppm 3.51(t,J=6.3Hz,2H)3.48(q,J=7.0Hz,2H)3.37(dt,J=12.9,2.6Hz,2H)2.97(td,J=13.0,3.1Hz,2H)1.96(d,J=14.3Hz,2H)1.73-1.83(m,1H)1.57(q,J=6.4Hz,2H)1.34-1.46(m,2H)1.18(t,J=7.0Hz,3H).MS(ESI+)m/z 158[M+H]+。
4-[4-(2-乙氧基乙基)哌啶-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.68(s,1H)7.67(d,J=9.2Hz,2H)7.01(d,J=9.2Hz,2H)3.98(d,J=13.1Hz,2H)3.40(t,J=6.7Hz,2H)3.40(q,J=7.0Hz,2H)2.88(td,J=12.7,2.4Hz,2H)1.73(d,J=12.8Hz,2H)1.59-1.69(m,1H)1.45(q,J=6.7Hz,2H)1.16(qd,J=12.2,3.8Hz,2H)1.10(t,J=7.0Hz,3H).MS(ESI+)m/z 262[M+H]+。
中间体113
4-(4-苄基-3-氧代哌嗪-1-基)苯甲醛
根据用于中间体103的程序制备标题产物,使用苄基溴代替1-溴-2-甲氧基乙烷。
4-苄基-3-氧代哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 7.32-7.37(m,2H)7.26-7.31(m,1H)7.26-7.29(m,2H)4.63(s,2H)4.12(s,2H)3.56-3.65(m,2H)3.31-3.33(m,2H)1.47(s,9H).MS(ESI+)m/z 291[M+H]+。
1-苄基哌嗪-2-酮三氟乙酸盐:1H NMR(600MHz,CD3OD)δppm 7.34-7.38(m,2H)7.31-7.34(m,2H)7.29-7.33(m,1H)4.67(s,2H)3.92(s,2H)3.51-3.55(m,2H)3.47-3.51(m,2H).MS(ESI+)m/z 191[M+H]+。
4-(4-苄基-3-氧代哌嗪-1-基)苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)7.72-7.75(m,2H)7.33-7.37(m,2H)7.26-7.30(m,3H)7.00-7.04(m,2H)4.61(s,2H)4.11(s,2H)3.66-3.69(m,2H)3.38-3.42(m,2H).MS(ESI+)m/z 295[M+H]+。
中间体114
4-(4-甲基-3-氧代哌嗪-1-基)苯甲醛
根据用于中间体103的程序制备标题产物,使用甲基碘代替1-溴-2-甲氧基乙烷。
4-甲基-3-氧代哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 4.01(s,2H)3.61-3.69(m,2H)3.37-3.42(m,2H)2.98(s,3H)1.47(s,9H).MS(ESI+)m/z 159[M+H-t-Bu]+。
1-甲基哌嗪-2-酮三氟乙酸盐:1H NMR(600MHz,CD3OD)δppm 3.83(s,2H)3.60-3.63(m,2H)3.51-3.55(m,2H)3.02(s,3H).MS(ESI+)m/z 115[M+H]+。
4-(4-甲基-3-氧代哌嗪-1-基)苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)7.72-7.75(m,2H)7.01-7.05(m,2H)3.98(s,2H)3.67-3.72(m,2H)3.44-3.48(m,2H)2.91(s,3H).MS(ESI+)m/z 219[M+H]+。
中间体115
4-[4-(吡啶-3-基羰基)哌嗪-1-基]苯甲醛
根据用于中间体104的程序制备标题产物,使用吡啶-3-碳酰氯代替甲氧基乙酰氯。
4-(吡啶-3-基羰基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 8.65(dd,J=4.96,1.67Hz,1H)8.64(dd,J=2.16,0.93Hz,1H)7.92(ddd,J=7.88,2.16,1.67Hz,1H)7.54(ddd,J=7.88,4.96,0.93Hz,1H)3.75(br.s.,2H)3.55(br.s.,2H)3.45(br.s.,4H)1.47(s,9H).MS(ESI+)m/z 292[M+H]+。
1-(吡啶-3-基羰基)哌嗪双(三氟乙酸盐):1H NMR(600MHz,CD3OD)δppm 8.70-8.76(m,2H)8.05(ddd,J=7.90,2.15,1.55Hz,1H)7.63(ddd,J=7.90,5.03,0.90Hz,1H)3.53-4.24(m,4H)3.33(br.s.,4H).MS(ESI+)m/z 192[M+H]+。
4-[4-(吡啶-3-基羰基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,CD3OD)δppm 9.72(s,1H)8.69(dd,J=2.14,0.76Hz,1H)8.67(dd,J=5.04,1.68Hz,1H)7.97(ddd,J=7.86,2.14,1.68Hz,1H)7.76-7.81(m,2H)7.56(ddd,J=7.86,5.04,0.76Hz,1H)7.05-7.09(m,2H)3.93(br.s.,2H)3.53-3.72(m,4H)3.48(br.s.,2H).MS(ESI+)m/z 296[M+H]+。
中间体116
4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯甲醛
根据用于中间体66的程序制备标题产物,使用N-(2-氯乙基)-1-甲基-1H-吡唑-5-胺代替2-溴乙基乙基醚。
4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 7.18(d,J=2.1Hz,1H)5.46(d,J=1.8Hz,1H)3.57(s,3H)3.45(br.s.,4H)3.23(t,J=6.7Hz,2H)2.63(t,J=6.6Hz,2H)2.48(t,J=5.0Hz,4H)1.46(s,9H).MS(ESI+)m/z310[M+H]+。
1-甲基-N-(2-哌嗪-1-基乙基)-1H-吡唑-5-胺:1H NMR(600MHz,CD3OD)δppm 7.18(d,J=2.1Hz,1H)5.46(d,J=2.1Hz,1H)3.57(s,3H)3.22(t,J=6.7Hz,2H)2.87(t,J=4.9Hz,4H)2.61(t,J=6.7Hz,2H)2.52(br.s.,4H).MS(ESI+)m/z 210[M+H]+。
4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯甲醛:1H NMR(600MHz,CD3OD)δppm 9.69(s,1H)7.76(d,J=9.2Hz,2H)7.19(d,J=2.1Hz,1H)7.04(d,J=9.2Hz,2H)5.49(d,J=2.1Hz,1H)3.58(s,3H)3.47(t,J=5.2Hz,4H)3.27(t,J=6.6Hz,2H)2.66-2.71(m,6H).MS(ESI+)m/z 314[M+H]+。
中间体117
4-[4-(吡啶-4-基羰基)哌嗪-1-基]苯甲醛
根据用于中间体104的程序制备标题产物,使用4-吡啶甲酰氯盐酸盐代替甲氧基乙酰氯。
4-(吡啶-4-基羰基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 8.65-8.68(m,2H)7.45-7.48(m,2H)3.70-3.78(m,2H)3.51-3.60(m,2H)3.40-3.48(m,2H)3.34-3.40(m,2H)1.47(s,9H).MS(ESI+)m/z 292[M+H]+。
1-(吡啶-4-基羰基)哌嗪双(三氟乙酸盐):1H NMR(600MHz,CD3OD)δppm 8.71-8.79(m,2H)7.59-7.66(m,2H)3.86-4.12(m,2H)3.52-3.81(m,2H)3.31-3.44(m,2H)3.20-3.32(m,2H).MS(ESI+)m/z 192[M+H]+。
4-[4-(吡啶-4-基羰基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.73(s,1H)8.68-8.72(m,2H)7.71-7.76(m,2H)7.43-7.47(m,2H)7.03-7.08(m,2H)3.71-3.83(m,2H)3.50-3.61(m,2H)3.36-3.50(m,4H).MS(ESI+)m/z 296[M+H]+。
中间体118
3-[4-(4-甲酰基苯基)哌嗪-1-基]丙腈
根据用于中间体66的程序制备标题产物,使用3-溴丙腈代替2-溴乙基乙基醚。
4-(2-氰基乙基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 3.30(t,J=4.9Hz,4H)2.67(t,J=6.1Hz,2H)2.57(t,J=6.1Hz,2H)2.36(t,J=5.2Hz,4H)1.39(s,9H).MS(ESI+)m/z 184[M+H-t-BuO]+。
3-哌嗪-1-基丙腈:1H NMR(600MHz,CD3OD)δppm 2.90(t,J=5.0Hz,4H)2.61-2.69(m,4H)2.53(br.s.,4H).MS(ESI+)m/z 140[M+H]+。
3-[4-(4-甲酰基苯基)哌嗪-1-基]丙腈:1H NMR(600MHz,DMSO-d6)δppm 9.72(s,1H)7.71(d,J=9.2Hz,2H)7.06(d,J=9.2Hz,2H)3.39(t,J=5.2Hz,4H)2.72(t,J=6.4Hz,2H)2.62(t,J=6.7Hz,2H)2.56(t,J=5.2Hz,4H).MS(ESI+)m/z 244[M+H]+。
中间体119
4-[4-(4-甲氧基丁基)哌嗪-1-基]苯甲醛
根据用于中间体66的程序制备标题产物,使用2-溴丁基甲基醚代替2-溴乙基乙基醚。
4-(4-甲氧基丁基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,DMSO-d6)δppm 3.30(t,J=6.4Hz,2H)3.28(br.s.,4H)3.21(s,3H)2.24-2.28(m,6H)1.40-1.51(m,4H)1.39(s,9H).MS(ESI+)m/z 273[M+H]+。
1-(4-甲氧基丁基)哌嗪:1H NMR(600MHz,CD3OD)δppm 3.39-3.43(m,2H)3.32(s,3H)2.84(t,J=4.9Hz,4H)2.46(br.s.,4H)2.34-2.38(m,2H)1.57(dt,J=6.9,3.4Hz,4H).MS(ESI+)m/z 173[M+H]+。
4-[4-(4-甲氧基丁基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm 9.71(s,1H)7.70(d,J=8.9Hz,2H)7.04(d,J=8.9Hz,2H)3.37(t,J=5.2Hz,4H)3.32(t,J=6.1Hz,2H)3.22(s,3H)2.46(t,J=5.2Hz,4H)2.31(t,J=7.0Hz,2H)1.44-1.56(m,4H).MS(ESI+)m/z 277[M+H]+。
中间体120
4-[4-(2,2-二甲基丙酰基)哌嗪-1-基]苯甲醛
根据用于中间体104的程序制备标题产物,使用新戊酰氯代替甲氧基乙酰氯。
4-(2,2-二甲基丙酰基)哌嗪-1-甲酸叔丁酯:1H NMR(600MHz,CD3OD)δppm 3.60-3.67(m,4H)3.39-3.47(m,4H)1.47(s,9H)1.28(s,9H).MS(ESI+)m/z 215[M+H-t-Bu]+。
1-(2,2-二甲基丙酰基)哌嗪三氟乙酸盐:1H NMR(600MHz,CD3OD)δppm 3.87-3.92(m,4H)3.21-3.25(m,4H)1.29(s,9H).MS(ESI+)m/z 171[M+H]+。
4-[4-(2,2-二甲基丙酰基)哌嗪-1-基]苯甲醛:1H NMR(600MHz,DMSO-d6)δppm9.73(s,1H)7.72-7.75(m,2H)7.02-7.06(m,2H)3.66-3.73(m,4H)3.37-3.42(m,4H)1.22(s,9H).MS(ESI+)m/z275[M+H]+。
中间体121
3-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯甲醛
根据用于中间体55的程序制备标题产物,使用1-(2-甲氧基乙基)哌嗪代替2-哌嗪-1-基乙醇,用3,4-二氟-苯甲醛代替4-氟苯甲醛。反应完全后,将反应混合物用DCM(2×30mL)萃取,并将合并的有机相真空浓缩,产生粗制产物,将其通过快速色谱(二氧化硅,4%MeOH/DCM)纯化。1H NMR(600MHz,DMSO-d6)δppm 9.81(d,J=1.5Hz,1H)7.67(dd,J=8.2,1.8Hz,1H)7.58(dd,J=13.7,1.8Hz,1H)7.16(t,J=8.5Hz,1H)3.46(t,J=5.8Hz,2H)3.24(s,3H)3.20(t,J=5.2Hz,4H)2.57(t,J=4.9Hz,4H)2.52(t,J=5.8Hz,2H).MS(ESI+)m/z267[M+H]+。
中间体122
3-甲氧基-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯甲醛
根据用于中间体121的程序制备标题产物,使用4-氟-3-甲氧基苯甲醛代替3,4-二氟苯甲醛。1H NMR(600MHz,DMSO-d6)δppm 9.81(s,1H)7.48(dd,J=8.1,1.7Hz,1H)7.35(d,J=1.5Hz,1H)7.02(d,J=8.2Hz,1H)3.85(s,3H)3.46(t,J=5.8Hz,2H)3.24(s,3H)3.13(br.s.,4H)2.56(br.s.,4H)2.52(t,J=6.1Hz,2H).MS(ESI+)m/z 279[M+H]+。
中间体123
2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯甲醛
根据用于中间体121的程序制备标题产物,使用2,4-二氟苯甲醛代替3,4-二氟苯甲醛。形成两种区域异构体,即标题产物和4-氟-2-[4-(2-甲氧基乙基)哌嗪-1-基]苯甲醛。通过快速色谱(二氧化硅,3%MeOH/DCM)纯化粗制物质,产生比例为77:23的异构体混合物,所需的异构体为主。该物质不经进一步纯化即用于下一步骤。1H NMR(600MHz,DMSO-d6)δppm9.92(s,1H)7.61(t,J=8.9Hz,1H)6.86(dd,J=8.9,2.1Hz,1H)6.79(dd,J=15.4,2.3Hz,1H)3.46(t,J=5.8Hz,2H)3.40(t,J=5.2Hz,4H)3.24(s,3H)2.49-2.52(m,6H).MS(ESI+)m/z 267[M+H]+。
4-氟-2-[4-(2-甲氧基乙基)哌嗪-1-基]苯甲醛(次要异构体):1H NMR(600MHz,DMSO-d6)δppm 10.05(s,1H)7.76(dd,J=8.9,7.0Hz,1H)7.00(dd,J=11.6,2.4Hz,1H)6.94(td,J=8.3,2.0Hz,1H)3.46(t,J=5.8Hz,2H)3.24(s,3H)3.05(t,J=4.9Hz,4H)2.61(br.s.,4H)2.55(t,J=5.8Hz,2H).MS(ESI+)m/z 267[M+H]+。
用于合成式(I)化合物的一般程序
实施例67
6-氯-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺
将5-氯-N4-(1-甲基哌啶-4-基)-3-硝基吡啶-2,4-二胺(中间体21,20.0mg,70μmol)和4-[4-(2-乙氧基乙基)哌嗪-1-基]苯甲醛(中间体41,18.4mg,70μmol)在EtOH(0.9mL)中制成浆,并添加新鲜制备的0.7M Na2S2O4水溶液(0.3mL,0.21mmol,3eq.)。将混合物在70℃下搅拌19小时。冷却至室温后,蒸发反应混合物,用DMSO稀释至约1.5mL,过滤并通过制备型RP-HPLC(碱性方法)纯化。合并纯的级分并蒸发,产生14.1mg(40%)纯标题产物,为白色固体。1H NMR(600MHz,DMSO-d6)δppm 12.96(br.s.,1H)7.98(d,J=8.9Hz,2H)7.87(s,1H)7.06(d,J=9.2Hz,2H)5.69(d,J=9.2Hz,1H)4.81-5.04(m,1H)3.51(t,J=6.0Hz,2H)3.43(q,J=7.0Hz,2H)3.25(t,J=5.2Hz,4H)2.81(d,J=11.3Hz,2H)2.56(t,J=4.9Hz,4H)2.52(t,J=6.0Hz,2H)2.21(s,3H)2.05(td,J=11.3,1.8Hz,2H)1.97(d,J=11.3Hz,2H)1.66(qd,J=11.6,3.8Hz,2H)1.11(t,J=7.0Hz,3H.MS(ESI+)m/z 498[M+H]+。
表1中显示了本发明化合物的实施例。
表1
上述实施例的分析数据如表2所示,其中指示的MS数据([M+H]+)通过ESI获得。
表2
生物学实施例
测量细胞毒性的方法
细胞活力测定提供了用于估计多孔板中存在的活细胞数的均一的荧光方法。该测定使用指示剂染料刃天青来测量细胞的代谢能力。活细胞保留将刃天青还原成为高度荧光的试卤灵的能力。非存活细胞迅速丧失代谢能力并且不会还原指示剂染料,因此不产生荧光信号。
将化合物储备溶液(10或100mM/DMSO)以1:2连续稀释为11个浓度,用EDC声学分配器(acoustic dispenser)在测定板中声学分配25nL/孔(100mM储备液)或50nL/孔(10mM储备液)。对于测试化合物,测定中的最终起始浓度为20μM(0.2%DMSO)或100μM(0.1%DMSO)。
将来自CLL患者或健康志愿者的周边血单核细胞(PBMC)接种在预分配有25μL/孔化合物的测定板(384-孔黑色/透明,Greiner#781091)中,培养24、48和72小时。对于来自CLL患者或健康志愿者的PBMC,细胞浓度为50 000细胞/孔。24、48和72h培养后,添加Celltiter Blue试剂(5μL/孔),并将板培养2小时。以Ex544nm/Em590nm在Envision荧光读取器(PerkinElmer)中读板。结果计算为与背景(用0.2%DMSO处理的细胞)相比的%细胞毒性。
表3中示出了在来自CLL患者和健康志愿者的PBMC中证明了对细胞毒性的作用的实施例。因此,表3中显示了本发明的一些化合物对于来自CLL患者以及健康志愿者的PBMC的细胞毒性的IC50值。
表3
Claims (15)
1.式(I′)或(I″)的化合物
或其药学上可接受的盐,其中
x是0至4的整数;
每个Ra独立地选自C1-C3烷基;
m是1或2;
R1是C1-C6烷基,C3-C6环烷基,C3-C6环烷基-C1-C6烷基,C1-C6烷基-C3-C6环烷基,C1-C6烷氧基-C1-C6烷基,氰基-C1-C6烷基,或式(II)的部分
其中
环A是苯基或含有1或2个选自N、O和S的杂原子的5元杂芳基;
g是0至3的整数;
每个R1a独立地选自C1-C6烷基,R1bO和R1cR1dN;
每个R1b独立地选自H和C1-C6烷基;
每个R1c独立地选自H和C1-C6烷基;
每个R1d独立地选自H和C1-C6烷基;或者
其中式(II)的部分是式(IIc)的部分
R2是Cl或Br;
p是0至3的整数;
每个R3独立地选自C1-C6烷基;
y是0至3的整数;
Rb选自卤素,C1-C3烷基和C1-C3烷氧基;
Z是N或CH;
W是>Q-R4,-O-或-N(R5)C(O)-;
Q是N或CH;
当W是>Q-R4或-O-时,n是1或2;
当W是-N(R5)C(O)-时,n是0或1;
R4是C1-C6烷基,R4a[O(CH2)q]r-Y,R4bS(O)2,R4cC(O),氰基-C1-C6烷基或式(III)的部分
每个q独立地选自1、2、3和4;
r是1或2;
h是0至3的整数;
Y是直接键或C(O);
L是直接键,C1-C4亚烷基或-L1-L2-;
L1是直接键或C1-C4亚烷基;
L2是C(O)或NH;
R4a是H或C1-C6烷基;
R4b是C1-C6烷基;
R4c是C1-C6烷基;
R4d是C1-C6烷基;
环B选自苯基和5或6元杂芳基,所述杂芳基含有1或2个选自N、O和S的杂原子;
R5是H,C1-C6烷基,R5a[O(CH2)u]v,或式(IV)的部分
R5a是H或C1-C6烷基;
每个u独立地选自1、2、3和4;
v是1或2;
M是直接键或C1-C4亚烷基;
环C是苯基;
R5b是C1-C6烷基;和
j是0至3的整数。
2.根据权利要求1所述的化合物或药学上可接受的盐,其中m为2。
3.根据权利要求1所述的化合物或药学上可接受的盐,其中当W为>Q-R4或-O-时,n为1;当W为-N(R5)C(O)-时,n为0。
5.根据权利要求1所述的化合物或药学上可接受的盐,其中W为>Q-R4或-N(R5)C(O)-。
6.根据权利要求5所述的化合物或药学上可接受的盐,其中W为>Q-R4。
7.根据权利要求1所述的化合物或药学上可接受的盐,其中R4是R4a[O(CH2)q]r-Y。
8.根据权利要求1所述的化合物或药学上可接受的盐,其中r为1。
9.根据权利要求1所述的化合物或药学上可接受的盐,其中Y是直接键。
10.根据权利要求1所述的化合物或药学上可接受的盐,其中Z为N。
12.根据权利要求1至11中任一项所述的化合物或药学上可接受的盐,具有式(I′)。
13.根据权利要求1所述的化合物,选自
6-溴-2-[4-(4-甲基哌嗪-1-基)苯基]-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-[4-(4-甲基哌嗪-1-基)苯基]-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-[4-(4-甲基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]乙醇,
2-[4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]乙醇,
2-[4-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]乙醇,
6-溴-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-[4-(4-乙基哌嗪-1-基)苯基]-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-[4-(4-乙基哌嗪-1-基)苯基]-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-[4-(4-乙基哌嗪-1-基)苯基]-N-(1-乙基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
2-{4-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}乙醇,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-[4-(4-乙基哌嗪-1-基)苯基]-N-[1-(4-甲氧基苄基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-[4-(4-吡啶-4-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-[4-(4-吡啶-4-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(1-甲基乙基)哌啶-4-基]-2-[4-(4-吡啶-4-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-[4-(4-吡啶-4-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(1-甲基乙基)哌啶-4-基]-2-[4-(4-吡啶-4-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-[4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基]-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-[4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基]-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-[4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基]-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-[4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基]-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-[4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-(4-吗啉-4-基苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-(4-吗啉-4-基苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(1-甲基乙基)哌啶-4-基]-2-(4-吗啉-4-基苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(1-甲基乙基)哌啶-4-基]-2-(4-吗啉-4-基苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-(4-吗啉-4-基苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-乙酰基哌嗪-1-基)苯基]-6-溴-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-乙酰基哌嗪-1-基)苯基]-6-氯-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-乙酰基哌嗪-1-基)苯基]-6-氯-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-乙酰基哌嗪-1-基)苯基]-6-溴-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-乙酰基哌嗪-1-基)苯基]-6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-2-酮,
4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-2-酮,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(甲基磺酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(甲基磺酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(1-甲基乙基)哌啶-4-基]-2-{4-[4-(甲基磺酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(1-甲基乙基)哌啶-4-基]-2-{4-[4-(甲基磺酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-{4-[4-(甲基磺酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(甲基磺酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(甲基磺酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
1-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1,4-二氮杂环庚烷-5-酮,
1-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1,4-二氮杂环庚烷-5-酮,
1-[4-(6-氯-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1,4-二氮杂环庚烷-5-酮,
1-[4-(6-溴-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1,4-二氮杂环庚烷-5-酮,
1-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1,4-二氮杂环庚烷-5-酮,
1-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1,4-二氮杂环庚烷-5-酮,
1-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1,4-二氮杂环庚烷-5-酮,
1-{4-[6-氯-7-({1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}氨基)-3H-咪唑并[4,5-b]吡啶-2-基]苯基}-1,4-二氮杂环庚烷-5-酮,
6-氯-2-[4-(4-甲基哌嗪-1-基)苯基]-N-{1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}-3H-咪唑并[4,5-b]吡啶-7-胺,
2-(4-{4-[6-氯-7-({1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}氨基)-3H-咪唑并[4,5-b]吡啶-2-基]苯基}哌嗪-1-基)乙醇,
6-氯-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-{1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-吗啉-4-基苯基)-N-{1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-乙酰基哌嗪-1-基)苯基]-6-氯-N-{1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(甲基磺酰基)哌嗪-1-基]苯基}-N-{1-[(1,3,5-三甲基-1H-吡唑-4-基)甲基]哌啶-4-基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-甲氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-甲氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-甲氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-{4-[4-(2-甲氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(2-甲氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-N-[1-(4-甲氧基苄基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-N-(1-乙基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-乙氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-N-[1-(4-甲氧基苄基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)-1,4-二氮杂环庚烷-1-基]苯基}-N-(1-乙基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-(4-{4-[2-(1-甲基乙氧基)乙基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(1-甲基乙氧基)乙基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(1-甲基乙氧基)乙基]哌嗪-1-基}苯基)-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-(4-{4-[2-(1-甲基乙氧基)乙基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-(4-{4-[2-(1-甲基乙氧基)乙基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
2-{4-[4-(6-氯-7-{[1-(噻吩-2-基甲基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}乙醇,
6-氯-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-[1-(噻吩-2-基甲基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-吗啉-4-基苯基)-N-[1-(噻吩-2-基甲基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-[4-(4-吡啶-4-基哌嗪-1-基)苯基]-N-[1-(噻吩-2-基甲基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-N-[1-(噻吩-2-基甲基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(1-甲基乙氧基)乙基]哌嗪-1-基}苯基)-N-[1-(噻吩-2-基甲基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
2-(4-{4-[6-氯-7-({1-[4-(二甲基氨基)苄基]哌啶-4-基}氨基)-3H-咪唑并[4,5-b]吡啶-2-基]苯基}哌嗪-1-基)乙醇,
6-氯-N-{1-[4-(二甲基氨基)苄基]哌啶-4-基}-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-{1-[4-(二甲基氨基)苄基]哌啶-4-基}-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-{1-[4-(二甲基氨基)苄基]哌啶-4-基}-2-(4-{4-[2-(1-甲基乙氧基)乙基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-(4-{4-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷-1-基}苯基)-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-(4-{4-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-(4-{4-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-(4-{4-[2-(1-甲基乙氧基)乙基]-1,4-二氮杂环庚烷-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-[4-(4-吡嗪-2-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-[4-(4-吡啶-3-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
4-({4-[(6-氯-2-{4-[4-(2-羟基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}甲基)-2-甲氧基苯酚,
4-({4-[(6-氯-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}甲基)-2-甲氧基苯酚,
2-{4-[4-(6-氯-7-{[1-(2,3-二氢-1-苯并呋喃-5-基甲基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}乙醇,
6-氯-N-[1-(2,3-二氢-1-苯并呋喃-5-基甲基)哌啶-4-基]-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(2,3-二氢-1-苯并呋喃-5-基甲基)哌啶-4-基]-2-{4-[4-(甲基磺酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(2,3-二氢-1-苯并呋喃-5-基甲基)哌啶-4-基]-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(1H-咪唑-4-基甲基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-(4-{4-[(6-甲基吡啶-2-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(1H-咪唑-4-基甲基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-(4-{4-[(6-甲基吡啶-2-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-(4-{4-[(3,5-二甲基异噁唑-4-基)甲基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(呋喃-2-基甲基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[(3,5-二甲基异噁唑-4-基)甲基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(呋喃-2-基甲基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
2-{4-[4-(6-氯-7-{[(3S)-1-甲基吡咯烷-3-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}乙醇,
6-氯-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-[(3S)-1-甲基吡咯烷-3-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-N-[(3S)-1-甲基吡咯烷-3-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[(3S)-1-甲基吡咯烷-3-基]-2-{4-[4-(吡啶-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[(3S)-1-甲基吡咯烷-3-基]-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[(3S)-1-甲基吡咯烷-3-基]-2-{4-[4-(吡啶-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
2-{4-[4-(6-氯-7-{[(3S)-1-丙基吡咯烷-3-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}乙醇,
6-氯-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-[(3S)-1-丙基吡咯烷-3-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[(3S)-1-丙基吡咯烷-3-基]-2-{4-[4-(吡啶-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[(3S)-1-丙基吡咯烷-3-基]-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[(3S)-1-丙基吡咯烷-3-基]-2-{4-[4-(吡啶-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(嘧啶-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(嘧啶-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-(4-{4-[(6-甲基吡啶-3-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-(4-{4-[(6-甲基吡啶-3-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡啶-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡啶-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-[4-(4-吡啶-3-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(1H-咪唑-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-(4-{4-[(6-甲基吡啶-2-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
2-{4-[4-(6-氯-7-{[(3S)-1-(4-甲氧基苄基)吡咯烷-3-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}乙醇,
6-氯-N-[(3S)-1-(4-甲氧基苄基)吡咯烷-3-基]-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[(3S)-1-(4-甲氧基苄基)吡咯烷-3-基]-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(1-甲基乙基)哌啶-4-基]-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(1-甲基乙基)哌啶-4-基]-2-{4-[4-(吡啶-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(1-甲基乙基)哌啶-4-基]-2-[4-(4-吡啶-3-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-(4-{4-[(3,5-二甲基异噁唑-4-基)甲基]哌嗪-1-基}苯基)-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(呋喃-2-基甲基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(1-甲基乙基)哌啶-4-基]-2-{4-[4-(嘧啶-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-[(3S)-1-甲基吡咯烷-3-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[(3S)-1-甲基吡咯烷-3-基]-2-{4-[4-(嘧啶-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[(3S)-1-甲基吡咯烷-3-基]-2-{4-[4-(吡啶-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[(3S)-1-甲基吡咯烷-3-基]-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[(3S)-1-甲基吡咯烷-3-基]-2-{4-[4-(吡啶-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[(3S)-1-甲基吡咯烷-3-基]-2-[4-(4-吡啶-3-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[(3S)-1-甲基吡咯烷-3-基]-2-[4-(4-吡嗪-2-基哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[(3,5-二甲基异噁唑-4-基)甲基]哌嗪-1-基}苯基)-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(呋喃-2-基甲基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(1-甲基乙基)哌啶-4-基]-2-{4-[4-(嘧啶-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(1-甲基乙基)哌啶-4-基]-2-(4-{4-[(6-甲基吡啶-3-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(1-甲基乙基)哌啶-4-基]-2-{4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(1-甲基乙基)哌啶-4-基]-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡啶-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-(4-{4-[(6-甲基吡啶-3-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-N-(1-乙基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(1H-咪唑-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
2-{4-[4-(6-溴-7-{[(3S)-1-甲基吡咯烷-3-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}乙醇,
6-溴-N-[(3S)-1-甲基吡咯烷-3-基]-2-{4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(呋喃-2-基甲基)哌嗪-1-基]苯基}-N-[(3S)-1-甲基吡咯烷-3-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[(3S)-1-甲基吡咯烷-3-基]-2-{4-[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(1H-咪唑-4-基甲基)哌嗪-1-基]苯基}-N-[(3S)-1-甲基吡咯烷-3-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-(4-{4-[(6-甲基吡啶-3-基)甲基]哌嗪-1-基}苯基)-N-[(3S)-1-甲基吡咯烷-3-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-(4-{4-[(6-甲基吡啶-2-基)甲基]哌嗪-1-基}苯基)-N-[(3S)-1-甲基吡咯烷-3-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[(5-甲基呋喃-2-基)甲基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-(4-{4-[(5-甲基呋喃-2-基)甲基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(呋喃-3-基甲基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(呋喃-3-基甲基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-(4-{4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-(4-{4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-基}苯基)-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-基}苯基)-N-[(3S)-1-甲基吡咯烷-3-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-基}苯基)-N-[1-(噻吩-3-基甲基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[2-(2-甲氧基乙氧基)乙基]哌嗪-1-基}苯基)-N-[1-(噻吩-2-基甲基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-甲氧基乙基)-3-甲基哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-甲氧基乙基)-3-甲基哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(2-甲氧基乙基)-3-甲基哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[3-甲基-4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[3-甲基-4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[3-甲基-4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-(4-{4-[(1-甲基-1H-咪唑-2-基)甲基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-(4-{4-[(1-甲基-1H-咪唑-2-基)甲基]哌嗪-1-基}苯基)-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-(4-{4-[(1-甲基-1H-咪唑-2-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-(4-{4-[(5-甲基吡啶-2-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-(4-{4-[(5-甲基吡啶-2-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-(4-{4-[(5-甲基吡啶-2-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-(4-{4-[(5-甲基吡啶-2-基)甲基]哌嗪-1-基}苯基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(3-甲氧基丙基)-3-甲基哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(3-甲氧基丙基)-3-甲基哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(3-甲氧基丙基)-3-甲基哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[3-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[3-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[3-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[2-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[2-甲基-4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-甲氧基乙基)-2-甲基哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-甲氧基乙基)-2-甲基哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-苄基哌嗪-1-基)苯基]-6-氯-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-苄基哌嗪-1-基)苯基]-6-溴-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
2-[4-(4-苄基哌嗪-1-基)苯基]-6-氯-N-(1-乙基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(3-甲氧基丙基)-2-甲基哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(3-甲氧基丙基)-2-甲基哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(3-甲氧基丙基)-2-甲基哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-甲氧基乙基)哌嗪-2-酮,
4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-甲氧基乙基)哌嗪-2-酮,
4-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-甲氧基乙基)哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(2-甲氧基乙基)哌嗪-2-酮,
4-[4-(6-溴-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(2-甲氧基乙基)哌嗪-2-酮,
4-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-甲氧基乙基)哌嗪-2-酮,
6-氯-2-{4-[4-(甲氧基乙酰基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(甲氧基乙酰基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(甲氧基乙酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(甲氧基乙酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(甲氧基乙酰基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(甲氧基乙酰基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(3-甲氧基丙基)哌嗪-2-酮,
4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(3-甲氧基丙基)哌嗪-2-酮,
4-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(3-甲氧基丙基)哌嗪-2-酮,
4-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(3-甲氧基丙基)哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(3-甲氧基丙基)哌嗪-2-酮,
4-[4-(6-溴-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(3-甲氧基丙基)哌嗪-2-酮,
4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-乙氧基乙基)哌嗪-2-酮,
4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-乙氧基乙基)哌嗪-2-酮,
4-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-乙氧基乙基)哌嗪-2-酮,
4-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-乙氧基乙基)哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(2-乙氧基乙基)哌嗪-2-酮,
4-[4-(6-溴-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(2-乙氧基乙基)哌嗪-2-酮,
2-[1-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌啶-4-基]乙醇,
2-[1-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌啶-4-基]乙醇,
2-[1-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌啶-4-基]乙醇,
2-[1-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌啶-4-基]乙醇,
2-{1-[4-(6-氯-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌啶-4-基}乙醇,
2-{1-[4-(6-溴-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌啶-4-基}乙醇,
4-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(2-甲氧基乙基)哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(2-乙氧基乙基)哌嗪-2-酮,
6-氯-2-{4-[4-(甲氧基乙酰基)哌嗪-1-基]苯基}-N-[1-(4-甲氧基苄基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
4-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(3-甲氧基丙基)哌嗪-2-酮,
2-{1-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌啶-4-基}乙醇,
6-氯-2-{4-[4-(甲氧基乙酰基)哌嗪-1-基]苯基}-N-[1-(噻吩-2-基甲基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
4-[4-(6-氯-7-{[1-(噻吩-2-基甲基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(3-甲氧基丙基)哌嗪-2-酮,
3-[4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]丙烷-1-醇,
3-[4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]丙烷-1-醇,
3-[4-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]丙烷-1-醇,
4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-[2-(1-甲基乙氧基)乙基]哌嗪-2-酮,
4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-[2-(1-甲基乙氧基)乙基]哌嗪-2-酮,
4-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-[2-(1-甲基乙氧基)乙基]哌嗪-2-酮,
4-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-[2-(1-甲基乙氧基)乙基]哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-[2-(1-甲基乙氧基)乙基]哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-[2-(1-甲基乙氧基)乙基]哌嗪-2-酮,
6-氯-2-{4-[4-(3-甲氧基丙酰基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(3-甲氧基丙酰基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(3-甲氧基丙酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(3-甲氧基丙酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-{4-[4-(3-甲氧基丙酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-甲氧基乙基)哌啶-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-甲氧基乙基)哌啶-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(2-甲氧基乙基)哌啶-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(2-甲氧基乙基)哌啶-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-甲氧基乙基)哌啶-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)哌啶-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-乙氧基乙基)哌啶-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(2-乙氧基乙基)哌啶-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(2-乙氧基乙基)哌啶-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-乙氧基乙基)哌啶-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
1-苄基-4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-2-酮,
1-苄基-4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-2-酮,
1-苄基-4-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-2-酮,
1-苄基-4-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-2-酮,
1-苄基-4-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-2-酮,
4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-甲基哌嗪-2-酮,
4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-甲基哌嗪-2-酮,
4-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-甲基哌嗪-2-酮,
4-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-甲基哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-甲基哌嗪-2-酮,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-3-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-3-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡啶-3-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡啶-3-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-{4-[4-(吡啶-3-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-N-(1-丙基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-N-(1-丙基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(2-甲氧基乙基)哌啶-4-基]-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
4-(4-{6-氯-7-[(1-丙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-乙氧基乙基)哌嗪-2-酮,
4-[4-(6-氯-7-{[1-(2-甲氧基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(2-乙氧基乙基)哌嗪-2-酮,
4-(4-{6-氯-7-[(1-环己基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-甲氧基乙基)哌嗪-2-酮,
3-[4-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]丙烷-1-醇,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-{4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-{4-[4-(1,3-噻唑-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-{4-[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(1,3-噻唑-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(1-甲基乙基)哌啶-4-基]-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-4-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-甲基哌啶-4-基)-2-{4-[4-(吡啶-4-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡啶-4-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(吡啶-4-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
3-[4-(4-{6-氯-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]丙腈,
3-[4-(4-{6-溴-7-[(1-甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]丙腈,
3-[4-(4-{6-氯-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]丙腈,
3-[4-(4-{6-溴-7-[(1-乙基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)哌嗪-1-基]丙腈,
3-{4-[4-(6-氯-7-{[1-(4-甲氧基苄基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}丙腈,
3-{4-[4-(6-溴-7-{[1-(1-甲基乙基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}丙腈,
6-溴-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-N-(1,2,2,6,6-五甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1,2,2,6,6-五甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1,2,2,6,6-五甲基哌啶-4-基)-2-{4-[4-(吡啶-3-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-N-(1,2,2,6,6-五甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
4-(4-{6-溴-7-[(1,2,2,6,6-五甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-乙氧基乙基)哌嗪-2-酮,
6-氯-2-{4-[4-(4-甲氧基丁基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(4-甲氧基丁基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{4-[4-(4-甲氧基丁基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{4-[4-(4-甲氧基丁基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(4-甲氧基苄基)哌啶-4-基]-2-{4-[4-(4-甲氧基丁基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-N-(1,2,2,6,6-五甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1,2,2,6,6-五甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1,2,2,6,6-五甲基哌啶-4-基)-2-{4-[4-(吡啶-3-基羰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-N-(1,2,2,6,6-五甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
4-(4-{6-氯-7-[(1,2,2,6,6-五甲基哌啶-4-基)氨基]-3H-咪唑并[4,5-b]吡啶-2-基}苯基)-1-(2-乙氧基乙基)哌嗪-2-酮,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
3-{4-[4-(6-氯-7-{[1-(环丙基甲基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}丙烷-1-醇,
4-[4-(6-氯-7-{[1-(环丙基甲基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(2-甲氧基乙基)哌嗪-2-酮,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{4-[4-(2,2-二甲基丙酰基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2,2-二甲基丙酰基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{4-[4-(2,2-二甲基丙酰基)哌嗪-1-基]苯基}-N-(1-乙基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(环丙基甲基)哌啶-4-基]-2-[4-(4-{2-[(1-甲基-1H-吡唑-5-基)氨基]乙基}哌嗪-1-基)苯基]-3H-咪唑并[4,5-b]吡啶-7-胺,
3-{4-[4-(6-溴-7-{[1-(环丙基甲基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]哌嗪-1-基}丙烷-1-醇,
4-[4-(6-溴-7-{[1-(环丙基甲基)哌啶-4-基]氨基}-3H-咪唑并[4,5-b]吡啶-2-基)苯基]-1-(2-甲氧基乙基)哌嗪-2-酮,
6-溴-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(2-乙氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(吡啶-3-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(1,3-噻唑-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{3-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{3-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{3-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{3-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{3-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(环丙基甲基)哌啶-4-基]-2-{3-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{3-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
{4-[(6-溴-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}乙腈,
{4-[(6-溴-2-{3-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}乙腈,
6-氯-2-{3-甲氧基-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{3-甲氧基-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{3-甲氧基-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{3-甲氧基-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{3-甲氧基-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(环丙基甲基)哌啶-4-基]-2-{3-甲氧基-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{3-甲氧基-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-2-{2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-(1-甲基哌啶-4-基)-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-(1-乙基哌啶-4-基)-2-{2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-(1-乙基哌啶-4-基)-2-{2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-溴-N-[1-(环丙基甲基)哌啶-4-基]-2-{2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-2-{2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-N-[1-(1-甲基乙基)哌啶-4-基]-3H-咪唑并[4,5-b]吡啶-7-胺,
3-{4-[(6-氯-2-{4-[4-(3-甲氧基丙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-氯-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-氯-2-{4-[4-(4-甲氧基丁基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-氯-2-{4-[4-(2,2-二甲基丙酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-氯-2-{4-[4-(3-羟基丙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-氯-2-{4-[4-(2-乙氧基乙基)-3-氧代哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-氯-2-{2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-溴-2-{4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-溴-2-{4-[4-(4-甲氧基丁基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-溴-2-{4-[4-(2,2-二甲基丙酰基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-溴-2-{4-[4-(3-羟基丙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-溴-2-{4-[4-(2-乙氧基乙基)-3-氧代哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
3-{4-[(6-溴-2-{2-氟-4-[4-(2-甲氧基乙基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-基)氨基]哌啶-1-基}丙腈,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(吡嗪-2-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(嘧啶-5-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,以及
6-氯-N-[1-(环丙基甲基)哌啶-4-基]-2-{4-[4-(吡啶-4-基甲基)哌嗪-1-基]苯基}-3H-咪唑并[4,5-b]吡啶-7-胺,
或其药学上可接受的盐。
14.药物组合物,其包含根据权利要求1至13中任一项所述的化合物或其药学上可接受的盐,和任选的药学上可接受的赋形剂。
15.根据权利要求1至13中任一项所述的化合物或药学上可接受的盐在制备药物中的用途,所述药物用于治疗选自淋巴瘤、白血病、肺癌、卵巢癌、胰腺癌、乳腺癌和成神经细胞瘤的过度增殖性失调。
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