CN114269742A - 作为治疗剂的4-(咪唑并[1,2-a]吡啶-3-基)-N-(吡啶基)嘧啶-2-胺的衍生物 - Google Patents
作为治疗剂的4-(咪唑并[1,2-a]吡啶-3-基)-N-(吡啶基)嘧啶-2-胺的衍生物 Download PDFInfo
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- CN114269742A CN114269742A CN202080054893.1A CN202080054893A CN114269742A CN 114269742 A CN114269742 A CN 114269742A CN 202080054893 A CN202080054893 A CN 202080054893A CN 114269742 A CN114269742 A CN 114269742A
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- Prior art keywords
- pyridin
- alkyl
- pyrimidin
- amino
- ethan
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- 239000003814 drug Substances 0.000 title claims description 14
- MWMKWQCXRZYXOK-UHFFFAOYSA-N 4-imidazo[1,2-a]pyridin-3-yl-N-pyridin-2-ylpyrimidin-2-amine Chemical class N=1C=C(N2C=1C=CC=C2)C1=NC(=NC=C1)NC1=NC=CC=C1 MWMKWQCXRZYXOK-UHFFFAOYSA-N 0.000 title description 3
- 229940124597 therapeutic agent Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 120
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 35
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 35
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 27
- 201000011510 cancer Diseases 0.000 claims abstract description 26
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims abstract description 25
- 230000002062 proliferating effect Effects 0.000 claims abstract description 24
- 238000011282 treatment Methods 0.000 claims abstract description 16
- 102000001253 Protein Kinase Human genes 0.000 claims abstract description 13
- 108060006633 protein kinase Proteins 0.000 claims abstract description 13
- 230000000694 effects Effects 0.000 claims abstract description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims description 189
- -1 NH)2) Chemical group 0.000 claims description 80
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 51
- 125000003118 aryl group Chemical group 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 45
- 229940002612 prodrug Drugs 0.000 claims description 37
- 239000000651 prodrug Substances 0.000 claims description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 32
- 239000012453 solvate Substances 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 22
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 19
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000003085 diluting agent Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 229910006069 SO3H Inorganic materials 0.000 claims description 9
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 9
- 125000002723 alicyclic group Chemical group 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 150000004885 piperazines Chemical class 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000000565 sulfonamide group Chemical group 0.000 claims description 7
- 230000035772 mutation Effects 0.000 claims description 6
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 6
- 150000003857 carboxamides Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 230000002018 overexpression Effects 0.000 claims description 4
- 230000003381 solubilizing effect Effects 0.000 claims description 4
- HGLGGZBCHGLPNS-UHFFFAOYSA-N tert-butyl 4-[4-[3-[2-[[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]amino]pyrimidin-4-yl]imidazo[1,2-a]pyridin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate Chemical compound C(C)(=O)N1CCN(CC1)C=1C=CC(=NC=1)NC1=NC=CC(=N1)C1=CN=C2N1C=C(C=C2)C=1C=NN(C=1)C1CCN(CC1)C(=O)OC(C)(C)C HGLGGZBCHGLPNS-UHFFFAOYSA-N 0.000 claims description 4
- 150000003230 pyrimidines Chemical class 0.000 claims description 3
- 150000003457 sulfones Chemical group 0.000 claims description 3
- 150000003462 sulfoxides Chemical group 0.000 claims description 3
- LVYNEBODCSGXCN-UHFFFAOYSA-N 1-[4-[6-[(4-imidazo[1,2-a]pyridin-3-ylpyrimidin-2-yl)amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound N=1C=C(N2C=1C=CC=C2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O LVYNEBODCSGXCN-UHFFFAOYSA-N 0.000 claims description 2
- ZJZLPSKTKWZOAN-UHFFFAOYSA-N 1-[4-[6-[[4-(6-anilinoimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound C1(=CC=CC=C1)NC=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O ZJZLPSKTKWZOAN-UHFFFAOYSA-N 0.000 claims description 2
- XQSQKPYZVPGSPG-UHFFFAOYSA-N 1-[4-[6-[[4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound ClC=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O XQSQKPYZVPGSPG-UHFFFAOYSA-N 0.000 claims description 2
- XKAMWEQXGJRFMD-UHFFFAOYSA-N 1-[4-[6-[[4-(6-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound CC=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O XKAMWEQXGJRFMD-UHFFFAOYSA-N 0.000 claims description 2
- GKYVVBPFZQMYDE-UHFFFAOYSA-N 1-[4-[6-[[4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound C1(=CC=CC=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O GKYVVBPFZQMYDE-UHFFFAOYSA-N 0.000 claims description 2
- NHHRNISUMUJJHH-UHFFFAOYSA-N 1-[4-[6-[[4-(6-pyridin-3-ylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound N1=CC(=CC=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O NHHRNISUMUJJHH-UHFFFAOYSA-N 0.000 claims description 2
- LMCPDYIAVYXKEL-UHFFFAOYSA-N 1-[4-[6-[[4-(6-thiophen-2-ylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound S1C(=CC=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O LMCPDYIAVYXKEL-UHFFFAOYSA-N 0.000 claims description 2
- GOOLGFAMQFBEOK-UHFFFAOYSA-N 1-[4-[6-[[4-(6-thiophen-3-ylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound S1C=C(C=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O GOOLGFAMQFBEOK-UHFFFAOYSA-N 0.000 claims description 2
- RGFWSXDSPJFZIM-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(1-benzofuran-2-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound O1C(=CC2=C1C=CC=C2)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O RGFWSXDSPJFZIM-UHFFFAOYSA-N 0.000 claims description 2
- LSXWPYPCVNGEAK-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(1-benzofuran-3-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound O1C=C(C2=C1C=CC=C2)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O LSXWPYPCVNGEAK-UHFFFAOYSA-N 0.000 claims description 2
- ZENAPHHCZKMHFY-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(1-benzothiophen-3-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound S1C2=C(C(=C1)C=1C=CC=3N(C=1)C(=CN=3)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O)C=CC=C2 ZENAPHHCZKMHFY-UHFFFAOYSA-N 0.000 claims description 2
- KCOUXWHHOCMREO-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(1-methylindol-3-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound CC(=O)N1CCN(CC1)C2=CN=C(C=C2)NC3=NC=CC(=N3)C4=CN=C5N4C=C(C=C5)C6=CN(C7=CC=CC=C76)C KCOUXWHHOCMREO-UHFFFAOYSA-N 0.000 claims description 2
- RTTYONMEAJGCOA-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(1-methylpyrazol-3-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound CN1N=C(C=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O RTTYONMEAJGCOA-UHFFFAOYSA-N 0.000 claims description 2
- BJYSEWMXIAHXEF-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(1H-indol-3-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound N1C=C(C2=CC=CC=C12)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O BJYSEWMXIAHXEF-UHFFFAOYSA-N 0.000 claims description 2
- QBCZXCANWUYVFT-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound N1N=CC(=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O QBCZXCANWUYVFT-UHFFFAOYSA-N 0.000 claims description 2
- DSSNTGIJEFEWLW-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(1H-pyrazol-5-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound N1N=C(C=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O DSSNTGIJEFEWLW-UHFFFAOYSA-N 0.000 claims description 2
- OVTHUIKJQWCPTP-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound N1C=C(C=2C1=NC=CC=2)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O OVTHUIKJQWCPTP-UHFFFAOYSA-N 0.000 claims description 2
- CMENUQMVUOYXTA-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(5-methylfuran-2-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound CC1=CC=C(O1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O CMENUQMVUOYXTA-UHFFFAOYSA-N 0.000 claims description 2
- GYDFIGPIHNUIKX-UHFFFAOYSA-N 1-[4-[6-[[4-[6-(furan-3-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound O1C=C(C=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O GYDFIGPIHNUIKX-UHFFFAOYSA-N 0.000 claims description 2
- APOZZRRFFVFCQT-UHFFFAOYSA-N 1-[4-[6-[[4-[6-[1-(difluoromethyl)pyrazol-4-yl]imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound FC(N1N=CC(=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O)F APOZZRRFFVFCQT-UHFFFAOYSA-N 0.000 claims description 2
- QTNNEWRHUPMTDT-UHFFFAOYSA-N 1-[4-[6-[[5-fluoro-4-(6-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl]amino]pyridin-3-yl]piperazin-1-yl]ethanone Chemical compound FC=1C(=NC(=NC=1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O)C1=CN=C2N1C=C(C=C2)C QTNNEWRHUPMTDT-UHFFFAOYSA-N 0.000 claims description 2
- PWCGDTMIVKOVLW-UHFFFAOYSA-N 4-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N-[5-(4-methylsulfonylpiperazin-1-yl)pyridin-2-yl]pyrimidin-2-amine Chemical compound BrC=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=NC=C(C=C1)N1CCN(CC1)S(=O)(=O)C PWCGDTMIVKOVLW-UHFFFAOYSA-N 0.000 claims description 2
- QWNISFJPCMUGHX-UHFFFAOYSA-N CC(=O)N1CCN(CC1)C2=CN=C(C=C2)NC3=NC=CC(=N3)C4=CN=C5N4C=C(C=C5)I Chemical compound CC(=O)N1CCN(CC1)C2=CN=C(C=C2)NC3=NC=CC(=N3)C4=CN=C5N4C=C(C=C5)I QWNISFJPCMUGHX-UHFFFAOYSA-N 0.000 claims description 2
- SACBDZFEMUZAGK-UHFFFAOYSA-N CN1N=CC(=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O Chemical compound CN1N=CC(=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O SACBDZFEMUZAGK-UHFFFAOYSA-N 0.000 claims description 2
- JXCGKZJVJYMXPJ-UHFFFAOYSA-N FC(C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O)(F)F Chemical compound FC(C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O)(F)F JXCGKZJVJYMXPJ-UHFFFAOYSA-N 0.000 claims description 2
- KXOCNHDHDFTAGU-UHFFFAOYSA-N N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine Chemical compound CN1CCN(CC1)C=1C=CC(=NC=1)NC1=NC=CC(=N1)C1=CN=C2N1C=C(C=C2)C1=CC=CC=C1 KXOCNHDHDFTAGU-UHFFFAOYSA-N 0.000 claims description 2
- QUFSHVOVDQKSQP-UHFFFAOYSA-N N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]-4-[6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-amine Chemical compound CN1N=CC(=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=NC=C(C=C1)N1CCN(CC1)C QUFSHVOVDQKSQP-UHFFFAOYSA-N 0.000 claims description 2
- WYKPRKNYYPRJGR-UHFFFAOYSA-N N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(6-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine Chemical compound C(C)N1CCN(CC1)CC=1C=CC(=NC=1)NC1=NC=C(C(=N1)C1=CN=C2N1C=C(C=C2)C1=CC=CC=C1)F WYKPRKNYYPRJGR-UHFFFAOYSA-N 0.000 claims description 2
- QMCHCWHCMAMKGN-UHFFFAOYSA-N N1C=C(C=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O Chemical compound N1C=C(C=C1)C=1C=CC=2N(C=1)C(=CN=2)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O QMCHCWHCMAMKGN-UHFFFAOYSA-N 0.000 claims description 2
- SSPAXCCVWVRHFA-UHFFFAOYSA-N S1C2=C(C=C1C=1C=CC=3N(C=1)C(=CN=3)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O)C=CC=C2 Chemical compound S1C2=C(C=C1C=1C=CC=3N(C=1)C(=CN=3)C1=NC(=NC=C1)NC1=CC=C(C=N1)N1CCN(CC1)C(C)=O)C=CC=C2 SSPAXCCVWVRHFA-UHFFFAOYSA-N 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims description 2
- 150000005255 pyrrolopyridines Chemical class 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
- 150000002475 indoles Chemical class 0.000 claims 1
- 150000003217 pyrazoles Chemical group 0.000 claims 1
- 150000003233 pyrroles Chemical group 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 108091007914 CDKs Proteins 0.000 abstract description 20
- 230000002401 inhibitory effect Effects 0.000 abstract description 8
- 230000004663 cell proliferation Effects 0.000 abstract description 6
- 230000002265 prevention Effects 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 157
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 154
- 238000005160 1H NMR spectroscopy Methods 0.000 description 148
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 145
- 230000015572 biosynthetic process Effects 0.000 description 116
- 238000003786 synthesis reaction Methods 0.000 description 114
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 112
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 100
- 238000006243 chemical reaction Methods 0.000 description 63
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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Abstract
用于预防和/或治疗包括癌症在内的增殖性疾病和病状的一类新型杂芳基化合物。认为所述化合物能够通过抑制FLT3及其突变形式和/或其他蛋白激酶如CDK的活性来抑制细胞增殖。所述化合物具有一般结构I:
Description
技术领域
本公开涉及一类新型蛋白激酶抑制剂,其可用于治疗包括癌症在内的增殖性细胞疾病和病状。
优先权文件
本申请要求2019年7月10日提交的题为“Inhibitors of protein kinases”的澳大利亚临时专利申请号2019902448的优先权,所述临时专利申请的内容通过引用整体并入本文。
背景技术
目前仍然需要鉴定和开发用于治疗包括癌症在内的增殖性疾病和病状的新化合物。其中研究的潜在抗增殖化合物的众多“靶标”是被称为蛋白激酶的酶组。
FMS样酪氨酸激酶3(FLT3),也称为CD135抗原和胎肝激酶-2(Flk2),在许多造血细胞表面表达,并且已知FLT3的信号传导在这些细胞的正常发育中起重要作用。FLT3或其突变的表达或过表达与某些癌症,特别是血癌(即血液学恶性肿瘤)相关。例如,在一些患有急性髓性白血病(AML)的患者的母细胞中已经发现高水平的FLT3(Zheng R等人,Blood103(1):267-274,2004),并且在急性淋巴细胞性白血病(ALL)和慢性淋巴细胞性白血病(CLL)中也已经发现异常的FLT3表达(RosnetO等人,Leukemia10:238-248,1996)。据推测,FLT3的异常表达或过量表达可能导致受体的组成型二聚化和活化(BraselK等人,Leukemia9:1212-1218,1995)。此外,已经鉴定出许多FLT3“活化”突变,最显著的是包含内部串联重复的FLT3-ITD突变(Nakao M等人,Leukemia10:1911-1918,1996),并且已知与患有AML的患者中非常差的预后相关(KottaridisPD等人,Blood 98(6):1752-1759,2001)。
许多FLT3抑制剂化合物已经或正在研究用于治疗血液恶性肿瘤诸如AML和其他FLT3活化的癌症。吉列替尼是美国食品和药物管理局(FDA)特别批准的有史以来第一种用于治疗患有复发性或难治性/突变FLT3、特别是FLT3-ITD或FLT3-TKD(酪氨酸激酶结构域中的突变)AML的AML患者的抑制剂药物。
细胞周期蛋白依赖性激酶(CDK)是另一类蛋白激酶。已知它们与各种细胞周期蛋白亚基相关,在细胞中各种重要的调控通路的调控中起关键作用,包括细胞周期控制、细胞凋亡、神经元生理机能、分化和转录。有超过20种CDK,可以分类为反应它们的功能的两大组:即细胞周期调控子CDK和转录调控子CDK。细胞周期调控子CDK的类别包括CDK1、CDK2、CDK3、CDK4和CDK6,并且它们与其细胞周期蛋白配偶体(例如细胞周期蛋白A、B、D1、D2、D3、E和F)起作用以调控细胞周期的促进。转录调控子CDK的类别包括CDK7、CDK8、CDK9和CDK11,它们与细胞周期蛋白C、H、K、L1、L2、T1和T2一起起作用,并且倾向于在转录调控中起作用。鉴于这两种CDK类别的功能,CDK与细胞增殖性疾病和病状,特别是癌症有关,也许就并不奇怪了。细胞增殖是细胞分裂周期直接或间接失调的后果,并且CDK在这个周期的各个阶段的调控中起关键作用。因此,CDK及其相关细胞周期蛋白的抑制剂被认为是癌症疗法的有用靶标。
先前已经研究将某些嘧啶基化合物用于治疗包括癌症在内的增殖性病症和病状,例如4-噻唑-2-吡啶基氨基-嘧啶和5-取代-4-噻唑-嘧啶(分别参见国际专利公开WO 2005/012298和WO2013/156780)。这些化合物抑制多种蛋白激酶,特别是CDK,包括CDK1/细胞周期蛋白B、CDK2/细胞周期蛋白E、CDK2/细胞周期蛋白A、CDK4/细胞周期蛋白D1、CDK6/细胞周期蛋白D3、CDK7/细胞周期蛋白H和CDK9/细胞周期蛋白T1。
本申请现在已经鉴定出用于预防和/或治疗包括癌症在内的增殖性疾病和病状的一类新的杂芳基化合物。虽然不希望受理论束缚,但是认为这些新型化合物能够通过抑制FLT3及其突变形式和/或其他蛋白激酶诸如CDK的活性来抑制细胞增殖。
发明内容
根据第一方面,本公开提供一种式I化合物:
其中:
R1、R2、R3、R4、R5和R6各自独立选自由以下组成的组:H、烷基、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环族基、杂芳基、杂环基、卤素、NO2、CN、CF3、OH、O-烷基、COR、COOR7、O-芳基、O-R7、NH2、NH-烷基、NH-芳基、N-(烷基)2、N-(芳基)2、N-(烷基)(芳基)、NH-R7、NH-烷基-N(烷基)2、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、COOH、CONH2、CONH-烷基、CONH-芳基、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SH-烷基、SO3H、SO2-烷基、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH2、SO2NH-R7、SO2N-(R7)(R8)、CO-烷基、CO-烷基-R7、CO-芳基、CO-芳基-R7和R9,其中所述烷基、芳基、芳烷基、脂环族基、杂芳基和杂环基任选地可以被一个或多个选自以下的基团取代:卤素、CN、OH、烷基(例如C1-6烷基)、O-C1-6烷基(例如O-甲基)、氨基(例如NH2)、COOH、CONH2、CF3CH(F)2或任选地被C1-6烷基、CH(F)2、COO-C1-6烷基(例如COO-C(CH3)3)或苯基磺酰基取代的杂环基;;
并且
R7、R8和R9独立地选自水增溶基团;
或其药学上可接受的盐、溶剂化物或前药。
在第二方面中,本公开提供了如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药用于治疗癌症或另外的增殖性病症或病状的用途。
在第三方面中,本公开提供了一种治疗受试者的癌症或另外的增殖性病症或病状的方法,所述方法包括向所述受试者施用治疗有效量的如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药,任选地组合有药学上可接受的载剂、稀释剂和/或赋形剂。
在第四方面中,本公开提供了如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药在制造用于治疗癌症或另一种的增殖性细胞疾病或病状的药剂中的用途。
在第五方面中,本公开提供了一种包含如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药和药学上可接受的载剂、稀释剂和/或赋形剂的药物组合物或药剂。
在第六方面中,本公开提供了一种用于调节细胞中蛋白激酶活性的方法,其包括向所述细胞中引入有效量的如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药,或者使所述细胞与有效量的如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药接触。
具体实施方式
本申请人现在已经鉴定出一类新的嘧啶-2-胺衍生物,特别是4-(咪唑并[1,2-a]吡啶-3-基)-N-(吡啶基)嘧啶-2-胺衍生物,其适用于预防和/或治疗包括癌症在内的增殖性病症和病状,其具有期望的生物活性(例如,所述化合物可以通过抑制细胞周期和转录CDK以及其他蛋白激酶如FLT3的活性来抑制细胞增殖并引起癌细胞凋亡)。
根据第一方面,本发明提供了下面所示的式I化合物:
其中:
R1、R2、R3、R4、R5和R6各自独立选自由以下组成的组:H、烷基、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环族基、杂芳基、杂环基、卤素、NO2、CN、CF3、OH、O-烷基、COR7、COOR7、O-芳基、O-R7、NH2、NH-烷基、NH-芳基、N-(烷基)2、N-(芳基)2、N-(烷基)(芳基)、NH-R7、NH-烷基-N(烷基)2、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、COOH、CONH2、CONH-烷基、CONH-芳基、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SH-烷基、SO3H、SO2-烷基、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH2、SO2NH-R7、SO2N-(R7)(R8)、CO-烷基、CO-烷基-R7、CO-芳基、CO-芳基-R7和R9,其中所述烷基、芳基、芳烷基、脂环族基、杂芳基和杂环基任选地可以被一个或多个选自以下的基团取代:卤素、CN、OH、烷基(例如C1-6烷基)、O-C1-6烷基(例如O-甲基)、氨基(例如NH2)、COOH、CONH2、CF3CH(F)2或任选地被C1-6烷基、CH(F)2、COO-C1-6烷基(例如COO-C(CH3)3)或苯基磺酰基取代的杂环基;
并且
R7、R8和R9独立地选自水增溶基团;
或其药学上可接受的盐、溶剂化物或前药。
在一些实施方案中,式I化合物可以优选包含至少一个水增溶基团R7、R8和R9。也就是说,在这样的实施方案中,所述化合物如前段中所限定,条件是所述化合物包含所述R7、R8和R9基团中的至少一个,或者更优选地,包含所述R7或R8基团中的至少一个。本申请人已经发现,尽管加了这一个或多个增溶基团,所述化合物仍具有期望的生物活性(例如通过抑制FLT3的活性)。至少一个水增溶基团的存在可以增强体内吸收和口服生物利用度。
已经发现式I化合物具有抗增殖活性,并因此被认为可用于治疗增殖性细胞疾病和病状,诸如癌症、白血病、淋巴瘤,以及其他与不受控制的细胞增殖相关(或者,换句话说,需要控制细胞循环)的疾病和病状,诸如一些心血管疾病或病状如再狭窄和心肌病、一些自身免疫疾病如肾小球肾炎和类风湿性关节炎、皮肤病状如牛皮癣、以及真菌性或寄生性病症。如本文所用,本发明的范围内的抗增殖作用可以通过在体外全细胞测定中抑制细胞增殖的能力来证明。这种测定的一个或多个实例(包括实施方法)在下文提供的实施例2中更详细地描述。
式I化合物可以抑制细胞周期中的任何步骤或阶段,例如核包膜的形成、从细胞周期的静止期(G0)退出、G1进展、染色体解聚、核包膜分解、START、DNA复制的引发、DNA复制的进展、DNA复制的终止、中心体复制、G2进展、有丝分裂或减数分裂功能的活化、染色体聚集、中心体分离、微管成核、纺锤体形成和功能、与微管动力蛋白的相互作用、染色单体分离和隔离、有丝分裂功能的失活、收缩环的形成和胞质分离功能。特别地,式I化合物可以影响某些基因功能,诸如染色质结合、复制复合体的形成、复制许可、磷酸化或其他二级修饰活性、蛋白水解性降解、微管结合、肌动蛋白结合、隔膜蛋白(septin)结合、微管组织中心成核活性和与细胞周期信号传导通路的结合。
因此,在第二方面中,本公开提供了如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药用于治疗癌症或另外的增殖性病症或病状的用途。
在第三方面中,本公开提供了一种治疗受试者的癌症或另外的增殖性病症或病状的方法,所述方法包括向所述受试者施用治疗有效量的如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药,任选地组合有药学上可接受的载剂、稀释剂和/或赋形剂。
在第四方面中,本公开提供了如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药在制造用于治疗癌症或另一种的增殖性细胞疾病或病状的药剂中的用途。
在第五方面中,本公开提供了一种包含如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药和药学上可接受的载剂、稀释剂和/或赋形剂的药物组合物或药剂。
在第六方面中,本公开提供了一种用于调节细胞中蛋白激酶活性的方法,其包括向所述细胞中引入有效量的如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药,或者使所述细胞与有效量的如第一方面中限定的化合物或其药学上可接受的盐、溶剂化物或前药接触。
优选地,第六方面的方法调节选自FLT3、FLT3-ITD的一种或多种蛋白激酶和一种或多种类型的FLT3点突变和/或其他蛋白激酶如CDK的活性。
在本说明书中,使用了本领域技术人员熟知的许多术语。然而,为了清楚起见,在下文中对许多这样的术语进行了定义。
如本文所用,术语“治疗”包括病状的预防以及病状的已确立症状的减轻。因此,“治疗”疾病或病状的行为包括:(1)预防或延迟患有所述疾病或病状或易患所述疾病或病状的受试者中所述疾病或病状发展的临床症状的出现;(2)抑制所述疾病或病状(即遏制、减少或延迟所述疾病或病状的发展或其复发(在维持治疗的情况下))或其至少一种临床或亚临床症状;以及(3)缓和或减缓所述疾病或病状(即导致疾病或病状或其临床或亚临床症状中的至少一种消退)。
如本文所用,术语“烷基”包括具有1至8个碳原子的直链烷基和支链烷基两种(例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基、环丙基、环丁基、环戊基等)。
如本文所用,术语“芳基”是指取代的(单取代的或多取代的)或未取代的单环芳族或多环芳族基团,其中所述多环芳族基团可以是稠合的或未稠合的。因此,所述术语包括具有6至10个碳原子的基团(例如苯基、萘基等)。还应理解,术语“芳基”与术语“芳族”同义。
如本文所用,术语“芳烷基”被用作如上限定的术语烷基和芳基的结合。
术语“脂肪族”采用其在本领域中的正常含义,并且包括非芳族基团,诸如烷烃、烯烃和炔烃以及其被取代的衍生物。
如本文所用,术语“脂环族”是指环状脂肪族基团。
术语“卤素”是指氟、氯、溴和碘。
如本文所用,术语“杂环”是指在环中包含一个或多个杂原子(例如N)的饱和或不饱和环状基团。
如本文所用的术语“衍生物”包括对实体的任何化学修饰。这类化学修饰的例证是氢被卤素基团、烷基、酰基或氨基置换。
如本文所用,短语“药剂的制造”包括将一种或多种式I化合物直接用作药剂,或者用在包含一种或多种式I化合物的药剂的制造的任何阶段中。
一些式I化合物可以单一立体异构体、外消旋体、和/或对映异构体和/或非对映异构体的混合物的形式存在。所有这类单一立体异构体、外消旋体及其混合物都包括在本公开的范围内。异构形式如非对映异构体、对映异构体和几何异构体可以通过本领域技术人员已知的物理和/或化学方法分离。
术语“前药”意指在生物系统内通常通过代谢手段(例如通过水解、还原或氧化)转化为式I化合物的化合物。例如,含羟基的式I化合物的酯前药可以通过体内水解转化为式I化合物。含羟基的式I化合物的合适酯可以是例如乙酸酯、柠檬酸酯、乳酸酯、酒石酸酯、丙二酸酯、草酸酯、水杨酸酯、丙酸酯、琥珀酸酯、富马酸酯、马来酸酯、亚甲基-双-对羟基萘甲酸酯、龙胆酸酯、羟乙磺酸酯、二对甲苯酰酒石酸酯、甲磺酸酯、乙磺酸酯、苯磺酸酯、对甲苯磺酸酯、环己基氨基磺酸酯和奎尼酸酯。作为另一个实例,含羧基的式I化合物的酯前药可以通过体内水解转化为式I化合物。酯前药的实例包括由Leinweber FJ,Drug Metab Rev18:379-439(1987)描述的那些前药。类似地,含氨基的式I化合物的酰基前药可以通过体内水解转化为式I化合物。Prodrugs:challenges and rewards,Valentino J Stella(编),Springer,2007中提供了针对这些和其他官能团(包括胺)的前药的实例。
如本文所用的术语“药学上可接受的盐”是指保留式I化合物的所需生物活性的盐,并且包括药学上可接受的酸加成盐和碱加成盐。式I化合物的合适药学上可接受的酸加成盐可以由无机酸或由有机酸制备。这类无机酸的实例是盐酸、硫酸和磷酸。适当的有机酸可以选自脂肪族、脂环族、芳族、杂环羧酸和磺酸类有机酸,其实例为甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡萄糖酸、乳酸、苹果酸、酒石酸、柠檬酸、富马酸、马来酸、烷基磺酸和芳基磺酸。关于药学上可接受的盐的额外信息可见于Remington's Pharmaceutical Sciences,第19版,Mack Publishing Co.,Easton,PA 1995。
在式I化合物为固体的情况下,本领域的技术人员将理解,所述化合物(或其药学上可接受的盐、溶剂化物或前药)可以不同的结晶或多晶型形式存在,所有这些形式都包括在本公开的范围内。
术语“治疗有效量”或“有效量”是足以实现有益的或所需的临床结果的量。治疗有效量可以以一次或多次施用来施用。通常,治疗有效量足以治疗疾病或病状,或者以其他方式缓和、改善、稳定、逆转、减慢或延迟疾病或病状如癌症或另一种的增殖性细胞疾病或病状的进展。仅作为举例,式I化合物或其药学上可接受的盐、溶剂化物或前药的治疗有效量可以介于约0.1mg/kg体重/日和约250mg/kg体重/日之间,更优选介于约0.1mg/kg体重/日至约100mg/kg体重/日之间,仍更优选介于约0.1mg/kg体重/日至约25mg/kg体重/日之间。然而,尽管如此,本领域技术人员将理解,治疗有效量可以变化并取决于多种因素,这些因素包括特定化合物(或其盐、溶剂化物或前药)的活性,特定化合物(或其盐、溶剂化物或前药)的代谢稳定性和作用时长,年龄,体重,性别,健康,施用途径与时间,特定化合物(或其盐、溶剂化物或前药)的排泄速率,以及例如待治疗的癌症或其他增殖性细胞疾病或病状的严重性。
能够抑制蛋白激酶的式I化合物及其药学上可接受的盐、溶剂化物和前药可以显示出对FLT3的选择性(即抑制)高于对一种或多种CDK的选择性。如上所述,FLT3通过其在细胞,特别是造血细胞的正常发育中的作用可以促进癌细胞增殖和抗细胞凋亡。因此,据信至少抑制FLT3的式I化合物及其药学上可接受的盐、溶剂化物和前药在体外应用和体内应用两者中(例如在基于细胞的体外测定中)都有效用,并且作为治疗受试者的癌症或另外的增殖性病症或病状的治疗方法的基础。
式I化合物可以带有至少一个水增溶基团(例如由R7、R8和/或R9提供)。术语“水增溶基团”将被本领域技术人员充分理解为是指任何极性官能团,其电离或能够与水分子形成氢键以增加化合物的水溶性(即相对于缺少水增溶基团的对应化合物的水溶性)。合适水增溶基团和方法的实例以及其引入的考虑因素描述于例如Gareth Thomas的Fundamentalsof Medicinal Chemistry(出版商:John Wiley&Sons)中。
优选地,在存在的情况下,R7和R8独立地选自由以下组成的组的水增溶基团:
(i)单羟基化、二羟基化和多羟基化的脂环族基团,二羟基化或多羟基化的脂肪族基团或芳基,被一个或多个羟基、氨基或烷氧基取代的含N、O和/或S的杂环基基团,包含一个或多个羧酰胺、亚砜、砜或磺酰胺基团的脂肪族基团和芳基,以及卤代烷基羰基;
和
(ii)COOH、SO3H、OSO3H、SONHCH3、SONHCH2CH3、SO2CH3、SO2CH2CH3、PO3H2和OPO3H2。
优选地,在存在的情况下,R9选自由以下组成的组的水增溶基团:
(i)单羟基化、二羟基化和多羟基化的脂环族基团,二羟基化或多羟基化的脂肪族基团或芳基,任选地被一个或多个以下基团取代的含N、O和/或S的杂环基:羟基、氨基或烷氧基,N(烷基)2,NH-烷基(任选地被一个或多个羟基或烷氧基取代),烷基-N(烷基)2,羰基,烷氧基,SO2-烷基,脂肪族基团(包括烷基),芳基,任选地包含一个或多个氨基、NH-烷基(任选地被一个或多个羟基或烷氧基取代)、羧酰胺、亚砜、砜或磺酰胺基团,任选地包含一个或多个烷基的杂环基,或任选地包含一个或多个烷基或羰基的NH-杂环基,并且其中所述含N、O和/或S的杂环基可以任选地包含连接到例如式I化合物的吡啶环的4/5位的碳原子的烷基桥(例如-CH2-或-CH2CH2-桥)、氨桥(例如-NH-、-NH-CH2-和-NH-CH2CH2-)、烷氧基桥(例如-O-CH2-和-O-CH2CH2-)或酮桥(例如-C(=O)-桥);和卤代烷基羰基;
(ii)COOH、SO3H、OSO3H、PO3H2和OPO3H2;
(iii)NHCO(CH2)m[NHCO(CH2)m']p[NHCO(CH2)m"]qA和NHCO(CH2)tNH(CH2)t'A,其中p和q各自独立地选自整数0或1,并且m、m’、m"、t和t’各自独立地选自整数1至10,并且A选自:
(a)包含一个或多个O、S或N杂原子的脂环族基、芳基和杂环基,其还可以包含烷基桥(例如-CH2-或-CH2CH2-桥),
(b)包含-O-、NH2、-NH-、=N-、季铵盐和脒中的一种或多种的脂环族基,以及
(c)吗啉基、哌嗪基或1,4-二氮杂环庚烷基,其中的每一种均可以任选地被一个或多个选自以下的取代基取代:SO2-烷基、任选地被一个或多个OH基团取代的烷基、CO-烷基、芳烷基、COO-烷基和任选地被一个或多个OH基团取代的醚基;
(iv)(CH2)nNR10COR11、(CH2)n'NR10SO2R11和SO2R12,其中R10选自H和烷基,R11和R12各自独立地选自任选地包含一个或多个杂原子并且/或者任选地被一个或多个独立地选自以下的取代基取代的烷基:OH、NH2、卤素和NO2,并且n和n’各自独立地选自整数0、1、2和3;
(v)醚和聚醚基团,其任选地被一个或多个OH基团或一个或多个A基团取代,其中A如上文(iii)处所定义;
(vi)(CH2)rNH2,其中r选自整数0、1、2和3;
(vii)(CH2)r'OH,其中r’选自整数0、1、2和3;
(viii)(CH2)n"NR13COR14,其中R13是H或烷基,n”选自整数0、1、2和3,并且R14是任选地被一个或多个选自以下的取代基取代的芳基:卤素、NO2、OH、烷氧基、NH2、COOH、CONH2和CF3;以及
(ix)SO2NR15R16,其中R15和R16各自独立地选自H、烷基和芳基,条件是R15和R16中的至少一者不是H,或者R15和R16一起形成任选地包含一个或多个选自N、O和S的杂原子的环状基团,并且其中所述烷基、芳基或环状基团任选地被一个或多个选自卤素、NO2、OH、烷氧基、NH2、COOH、CONH2和CF3的取代基取代。
在一些实施方案中,R1和R2各自独立地选自由以下组成的组:H、烷基、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环族基、杂芳基、杂环基、卤素、NO2、CN、CF3、OH、O-烷基、COR7、COOR7、O-芳基、O-R7、NH2、NH-烷基、NH-芳基、N-(烷基)2、N-(芳基)2、N-(烷基)(芳基)、NH-R7、NH-烷基-N(烷基)2、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、COOH、CONH2、CONH-烷基、CONH-芳基、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SH-烷基、SO3H、SO2-烷基、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH2、SO2NH-R7、SO2N-(R7)(R8)、CF3、CO-烷基、CO-烷基-R7、CO-芳基、CO-芳基-R7和R9,其中所述烷基、芳基、芳烷基、脂环族基、杂芳基和杂环基可以任选地被一个或多个选自以下的基团取代:卤素、CN、OH、C1-6烷基、O-C1-6烷基(例如O-甲基)、氨基(例如NH2)、COOH、CONH2、CF3CH(F)2或任选地被C1-6烷基、CH(F)2、COO-C1-6烷基(例如COO-C(CH3)3)或苯基磺酰基取代的杂环基;并且R3、R4、R5和R6各自独立地选自由以下组成的组:H、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环族基、杂环基、CF3、COR7、COOR7、O-芳基、O-R7、NH-芳基、N-(芳基)2、N-(烷基)(芳基)、NH-R7、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、CONH-烷基、CONH-芳基、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SO3H、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH-R7、SO2N-(R7)(R8)、CO-烷基-R7、CO-芳基、CO-芳基-R7和R9,其中所述烷基、芳基、芳烷基、脂环族基和杂环基可以任选地被一个或多个选自以下的基团取代:卤素、CN、OH、O-甲基、NH2、COOH、CONH2和CF3。
在一些实施方案中,R1为H、烷基(例如C1-6烷基,或优选地,C1-3烷基,诸如甲基、乙基,和C(CH3)2)、芳基、CN、CF3、NH2、杂芳基、任选取代的杂环基(例如包含一个或两个N、O或S杂原子的饱和或不饱和的5-或6-元环状基团)、O-烷基(例如O-C1-3烷基,诸如O-CH3)、NH-烷基(例如NH-C1-6烷基,诸如NH(C5H9)(即NH-环戊基),或优选地,NH-C1-3烷基如NH-CH3)、NH-烷基-N(烷基)2(例如NH-烷基-(C1-6烷基)2,诸如NH(C1-3烷基)-N(C1-3烷基)2)、NH-芳基、N-(烷基)2如N(CH3)2、N-(烷基)(芳基)、SH-烷基(例如SH-C1-6烷基,或优选地,SH-C1-3烷基,诸如SHCH3和SHC(CH3))、卤素(优选F、Br或Cl)或R9。在R1为R9的情况下,R9优选为单羟基化、二羟基化或多羟基化的脂环族基,或被一个或多个羟基、氨基或烷氧基取代的含N、O和/或S的杂环基。最优选地,R1为H,C1-3烷基如甲基,芳基,CF3,任选地被以下基团取代的杂环基:C1-6烷基、O-C1-6烷基(例如O-甲基)、氨基(例如NH2)、CH(F)2、苯基磺酰基或任选地被C1-6烷基取代的哌嗪(例如任选地被C1-6烷基取代的哌嗪,任选地被C1-6烷基取代的吡啶,任选地被C1-6烷基、O-甲基、NH2或任选地被C1-6烷基、CH(F)2取代的任选地被取代的哌嗪、吡咯、吡唑取代的嘧啶,或任选地被COO-C1-6烷基(例如COO-C(CH3)3)取代的哌嗪,任选地被C1-6烷基取代且包括双环结构的噻吩基、呋喃,如苯并呋喃、苯并噻吩基,任选地被C1-6烷基或苯基磺酰基取代的吲哚,和任选地被苯基磺酰基)、O-C1-6烷基(例如O-甲基)、氨基(例如NH2)、NH-芳基或卤素(优选地,F或Br)取代的吡咯并吡啶。
在一些实施方案中,R2为H、烷基(例如C1-6烷基,或优选地,C1-3烷基如甲基或乙基)、CN或卤素(优选F)。
在一些实施方案中,R3、R4、R5和R6中的至少一者,但优选R4或R5,为C1-6烷基,或优选地,C1-3烷基如甲基、卤素、烷基-R7(例如C1-3烷基-R7),其中R7优选选自COOH、SO3H、OSO3H、SONHCH3、SONHCH2CH3、SO2CH3、SO2CH2CH3、PO3H2和OPO3H2,但更优选为SONHCH3或SONHCH2CH3、NH-R7,其中R7优选选自COOH、SO3H、OSO3H、SONHCH3、SONHCH2CH3、SO2CH3、SO2CH2CH3、PO3H2和OPO3H2,但更优选为SO2CH3或SO2CH2CH3,或为R9,其中R9优选为被一个或多个羟基、氨基或烷氧基(例如-OCH3)基团取代的含N、O和/或S的杂环基。优选地,所述一个或多个杂原子为N。
在一些实施方案中,在R3、R5和R6为H的情况下,除COOH外,R4优选为C(=O)NHOH、C(=O)NHO-四氢吡喃或被NH2取代的CONH-芳基。
在一些实施方案中,在R3、R4、R5和R6中至少一者为R9的情况下,R9优选选自以下:
任选地,前段中示出的R9取代基还可以包含连接到吡啶环的4/5位的碳原子的烷基桥(例如-CH2-或-CH2CH2-桥)、氨基桥(例如-NH-)、烷氧基桥(例如-O-CH2-)或酮桥(例如-C(=O)-桥)。
在R3为R9的情况下,R4、R5和R6优选为H。类似地,在R4为R9的情况下,R3、R5和R6优选为H。此外,在R5为R9的情况下,R3、R4和R6优选为H。并且,在R6为R9的情况下,R3、R4和R5优选为H。
在一些实施方案中,R3和R6为H。
在一些特别优选的实施方案中,R3、R5和R6各自为H,并且R4为R9,其中R9为:
在一些其他优选的实施方案中,所述化合物具有式II:
其中n为0或1,R1、R2、R3、R4、R5和R6如上面关于式I所定义;并且
R17选自H、烷基(例如C1-6烷基,或优选地,C1-3烷基如甲基或乙基)、烷氧基(例如-OCH3或-OCH2CH3)、羰基(例如酮基如CO-CH3或羧酸酯基如COO-C(CH3)3)、甲基磺酰基、NH-烷基(例如N(CH3)2)和羧酰胺(例如CONH2)。
在一些优选的实施方案中,所述化合物选自由以下组成的组:
1-(4-(6-((4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((5-氟-4-(6-甲基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺;
N-(5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-基)-5-氟-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺;
1-(4-(6-((4-(6-氯咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-甲基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯并[b]噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1H-吡咯-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(呋喃-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(噻吩-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯基氨基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯并呋喃-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯并[b]噻吩-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1-甲基-1H-吲哚-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1H-吲哚-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1H-吡咯并[2,3-b]吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-碘咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺;
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-基)嘧啶-2-胺;
N-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺;
1-(4-(6-((4-(6-(1H-吡唑-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1-甲基-1H-吡唑-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1-(二氟甲基)-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
4-(4-(3-(2-((5-(4-乙酰基哌嗪-1-基)吡啶-2-基)氨基)嘧啶-4-基)咪唑并[1,2-a]吡啶-6-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯;
1-(4-(6-((4-(6-(5-甲基呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;和
4-(6-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)嘧啶-2-胺。
在一些优选的实施方案中,本公开的化合物在人细胞系中展现出抗增殖活性,如通过标准细胞毒性测定所测量的。优选地,所述化合物展现出如通过下文实施例2中所述的细胞活力测定所测量的小于5μM,甚至更优选小于1μM的IC50值。仍更优选地,所述化合物展现出小于0.5μM的IC50值。
在一些优选的实施方案中,本公开的化合物抑制一种或多种蛋白激酶,如通过本领域技术人员熟知的任何标准测定所测量的。优选地,所述化合物展现出如通过下文实施例2中所述的激酶测定所测量的小于1μM或小于0.5μM的IC50值,仍更优选小于0.1μM。
根据第一方面的化合物的特定实例示于下表1中。
表1本公开的所选化合物的化学结构
化合物(及其药学上可接受的盐、溶剂化物和前药)可以与一种或多种用于治疗癌症或另外的增殖性疾病或病状的额外剂组合施用。例如,所述化合物可以与其他抗癌剂组合使用,以同时抑制多于一种癌症信号传导通路,从而使癌细胞对抗癌疗法(例如,用其他抗癌剂、化疗、放疗或其组合进行的治疗)更敏感。因此,式I化合物可以与以下类别的抗癌剂中的一种或多种组合使用:
·如医学肿瘤学中所用的其他抗增殖/抗肿瘤药物及其组合,诸如烷化剂(例如顺铂、奥沙利铂、卡铂、环磷酰胺、氮芥、美法仑、苯丁酸氮芥、白消安、替莫唑胺和亚硝基脲);抗代谢药(例如吉西他滨和抗叶酸剂,诸如氟嘧啶类如5-氟尿嘧啶和替加氟、雷替曲塞、甲氨蝶呤、胞嘧啶阿拉伯糖苷、氟达拉滨和羟基脲);抗肿瘤抗生素(例如蒽环类药物,诸如阿霉素、博来霉素、多柔比星、道诺霉素、表柔比星、伊达比星、丝裂霉素-C、放线菌素D和光神霉素);抗有丝分裂剂(例如长春花生物碱,诸如长春新碱、长春花碱、长春地辛和长春瑞滨,以及紫杉烷类,包括紫杉醇和多西他赛以及保罗激酶(polokinase)抑制剂);以及拓扑异构酶抑制剂(例如表鬼臼毒素类,诸如依托泊苷和替尼泊苷、安吖啶、拓扑替康和喜树碱);
·细胞抑制剂,诸如抗雌激素(例如他莫西芬、氟维司群、托瑞米芬、雷洛昔芬、屈洛昔芬和艾多昔芬(iodoxyfene))、抗雄激素(例如比卡鲁胺、氟他胺、尼鲁米特(nilutamide)和醋酸环丙孕酮)、LHRH拮抗剂或LHRH激动剂(例如戈舍瑞林、亮丙瑞林和布舍瑞林)、孕激素(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿那曲唑、来曲唑、伏拉唑(vorazole)和依西美坦)和5α-还原酶的抑制剂如非那雄胺;
·抗侵袭剂(例如c-Src激酶家族抑制剂,诸如4-(6-氯-2,3-亚甲基二氧苯胺基)-7-[2-(4-甲基哌嗪-1-基)乙氧基]-5-四氢吡喃-4-基氧基喹唑啉(AZD0530;国际专利申请号WO 01/94341)、N-(2-氯-6-甲基苯基)-2-{6-[4-(2-羟乙基)哌嗪-1-基]-2-甲基嘧啶-4-基氨基}噻唑-5-羧酰胺(达沙替尼)和博舒替尼(bosutinib)(SKI-606))以及金属蛋白酶抑制剂(包括马立马司他(marimastat))、尿激酶纤溶酶原活化剂受体功能的抑制剂或肝素酶的抗体;
·生长因子功能抑制剂(例如生长因子抗体和生长因子受体抗体,诸如抗erbB2抗体曲妥珠单抗(HerceptinTM)、抗EGFR抗体帕尼单抗(panitumumab)、抗erbB1抗体西妥昔单抗(爱必妥,C225)和Stern等人Critical reviews in oncology/haematology,2005,第54卷,第11-29页)公开的任何生长因子或生长因子受体抗体。这类抑制剂还包括酪氨酸激酶抑制剂,诸如表皮生长因子家族的抑制剂(例如EGFR家族酪氨酸激酶抑制剂,诸如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺(吉非替尼,ZD1839)、N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼,OSI 774)和6-丙烯酰胺基-N-(3-氯-4-氟苯基)-7-(3-吗啉代丙氧基)-喹唑啉-4-胺(CI 1033)、erbB2酪氨酸激酶抑制剂如拉帕替尼);肝细胞生长因子家族的抑制剂;胰岛素生长因子家族的抑制剂;血小板源性生长因子家族的抑制剂,诸如伊马替尼和/或尼洛替尼(AMN107);丝氨酸/苏氨酸激酶的抑制剂(例如Ras/Raf信号传导抑制剂,诸如法尼基转移酶抑制剂,包括索拉非尼(BAY 43-9006)、替吡法尼(tipifarnib)(R115777)和洛那法尼(lonafarnib)(SCH66336))、通过MEK和/或AKT激酶的细胞信号传导的抑制剂、c-kit抑制剂、abl激酶抑制剂、PI3激酶抑制剂、Plt3激酶抑制剂、CSF-1R激酶抑制剂、IGF受体(胰岛素样生长因子)激酶抑制剂;极光激酶抑制剂(例如AZD1152、PH739358、VX-680、MLN8054、R763、MP235、MP529、VX-528和AX39459)以及细胞周期蛋白依赖性激酶抑制剂如CDK2和/或CDK9抑制剂;
·抗血管生成剂,诸如抑制血管内皮生长因子作用的抗血管生成剂(例如抗血管内皮细胞生长因子抗体贝伐珠单抗(AvastinTM)和VEGF受体酪氨酸激酶抑制剂,诸如凡德他尼(vandetanib)(ZD6474)、瓦他拉尼(vatalanib)(PTK787)、舒尼替尼(SU11248)、阿昔替尼(AG-013736)、帕唑帕尼(GW 786034)和4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯烷-1-基丙氧基)喹唑啉(AZD2171;国际专利公开号WO 00/47212内的实施例240),诸如国际专利公开号WO97/22596、WO 97/30035、WO 97/32856和WO 98/13354中公开的那些的化合物,以及通过其他机制起作用的化合物(例如利诺胺(linomide)、整联蛋白αvβ3功能的抑制剂和血管抑素);
·血管损伤剂,诸如康普瑞汀(Combretastatin)A4和国际专利公开号WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434和WO 02/08213中公开的化合物;
·内皮素受体拮抗剂,诸如齐泊腾坦(zibotentan)(ZD4054)或阿曲生坦(atrasentan);
·反义疗法,诸如针对上文所列的靶标的那些,诸如ISIS 2503,其是一种抗ras反义物;
·基因治疗方法,包括例如置换异常基因如异常p53或异常BRCA1或BRCA2的方法,GDEPT(基因导向酶前药疗法)方法如使用胞嘧啶脱氨酶、胸苷激酶或细菌硝基还原酶的那些方法,以及增加患者对化疗或放疗的耐受性的方法如多药抗性基因疗法;以及
·免疫治疗方法,包括例如增加患者肿瘤细胞的免疫原性的离体和体内方法(诸如用诸如白介素2、白介素4的细胞因子或粒细胞-巨噬细胞集落刺激因子转染)、降低T细胞失能的方法、使用转染的免疫细胞如细胞因子转染的树突细胞的方法、使用细胞因子转染的肿瘤细胞系的方法以及使用抗独特型抗体的方法。
在与其他抗癌剂组合使用的情况下,本公开的化合物和其他抗癌剂可以以同一药物组合物施用或者以分开的药物组合物施用。如果以分开的药物组合物施用,则所述化合物和其他抗癌剂可以同时或以任意顺序(例如在数秒或数分钟或甚至数小时(例如2至48小时)内)相继施用。
本公开的化合物通常适用于治疗人受试者的癌症或另一种的增殖性细胞疾病或病状。然而,所述受试者也可以选自例如牲畜(例如牛、马、猪、绵羊和山羊)、伴侣动物(例如狗和猫)以及野外动物(例如非人灵长类动物、老虎、大象等)。
可以根据本公开治疗的癌症和其他增殖性细胞疾病和病状包括胆道癌、脑癌和中枢神经系统(CNS)的其他癌症(包括成神经胶母细胞瘤和髓母细胞瘤)、成神经细胞瘤、乳腺癌、宫颈癌、卵巢癌(包括由上皮细胞、基质细胞、生殖细胞和间充质细胞引起的那些癌症)、绒毛膜癌、结肠直肠癌、子宫内膜癌、肝癌、肺癌、食道癌、胃癌、血液肿瘤(包括急性淋巴细胞性白血病(ALL))、慢性淋巴细胞性白血病(CLL)和慢性髓细胞性白血病(CML)以及急性髓性白血病(AML)、多发性骨髓瘤、AIDS相关性白血病和成人T细胞白血病淋巴瘤、淋巴瘤(包括非霍奇金淋巴瘤、霍奇金病和淋巴细胞性淋巴瘤)、上皮内肿瘤(包括鲍温(Bowen)病和佩吉特氏病)、口腔癌(包括鳞状细胞癌)、胰腺癌、前列腺癌、肉瘤(包括平滑肌肉瘤、横纹肌肉瘤、脂肪肉瘤、纤维肉瘤和骨肉瘤)、皮肤癌(包括黑色素瘤、卡波西肉瘤、基底细胞癌和鳞状细胞癌)、睾丸癌(包括生发肿瘤,诸如精原细胞瘤、非精原细胞瘤畸胎瘤和绒毛膜癌)、间质瘤、生殖细胞肿瘤、甲状腺癌(包括甲状腺腺癌和髓样癌)和肾癌(包括腺癌和威尔姆斯肿瘤)。
在一些实施方案中,本公开的化合物用于治疗癌症,所述癌症的特征在于FLT3或FLT3-ITD(一种突变形式,包括在一些患有急性髓性白血病(AML)的患者中与非常差的预后相关的内部串联重复)表达或过表达,包括例如若干血液恶性肿瘤(Stirewalt DL和JPRadich,Nat Rev Cancer 3:650-665(2003),诸如AML和其他FLT3活化的癌症。FLT3过表达可以通过例如使用本领域技术人员熟知的任何技术(例如定量扩增技术如qPCR)评估合适样品中编码FLT3的mRNA的量来确定。
本公开的化合物可以与药学上可接受的载剂、稀释剂和/或赋形剂一起配制成药物组合物。合适的载剂和稀释剂的实例是本领域技术人员熟知的,并且描述于例如Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,PA 1995中。用于本文所述的各种不同形式的药物组合物的合适赋形剂的实例可见于Handbook ofPharmaceutical Excipients,第2版,(1994),由AWade和PJ Weller编辑。合适载剂的实例包括乳糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、甘露糖醇、山梨糖醇等。合适稀释剂的实例包括乙醇、甘油和水。可以关于预期的施用途径和标准的药学实践进行载剂、稀释剂和/或赋形剂的选择。
包含本公开的化合物的药物组合物还可以包含任何合适的粘合剂、润滑剂、悬浮剂、包衣剂和增溶剂。合适粘合剂的实例包括淀粉、明胶、天然糖如葡萄糖、无水乳糖、自由流动的乳糖、β-乳糖、玉米甜味剂、天然和合成树胶如阿拉伯树胶、黄蓍胶或海藻酸钠、羧甲基纤维素和聚乙二醇。合适润滑剂的实例包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。可以在药物组合物中提供防腐剂、稳定剂、着色剂乃至调味剂。防腐剂的实例包括苯甲酸钠、山梨酸和对羟基苯甲酸的酯。还可以使用抗氧化剂和悬浮剂。
包含本公开的化合物的药物组合物可以适于经口、经直肠、经阴道、肠胃外、肌内、腹膜内、动脉内、鞘内、支气管内、皮下、皮内、静脉内、经鼻、经颊或舌下施用途径。对于经口施用,可以特别使用压制片剂、丸剂、片剂、凝胶剂、滴剂和胶囊。对于其他施用形式,药物组合物可以包括可以静脉内、动脉内、鞘内、皮下、皮内、腹膜内或肌内注射并且由无菌或可灭菌的溶液制备的溶液或乳液。包含本公开的化合物的药物组合物还可以是栓剂、阴道栓、混悬剂、乳剂、洗剂、膏剂、霜剂、凝胶剂、喷雾剂、溶液或扑粉剂的形式。药物组合物可以按单位剂型(即,以含有单位剂量或多个单位剂量或单位剂量亚单位的离散部分的形式)配制。
本公开的化合物可以作为包括例如其合适的酸加成盐或碱式盐的药学上可接受的盐提供。合适药用盐的综述可见于Berge等人,JPharm Sci 66:1-19(1977)中。盐是例如用以下物质形成的:强无机酸,诸如矿物酸(例如硫酸、磷酸或氢卤酸);强有机羧酸,诸如未取代的或(例如被卤素)取代的1至4个碳原子的烷烃羧酸如乙酸;饱和或不饱和的二元羧酸(例如草酸、丙二酸、琥珀酸、马来酸、富马酸、邻苯二甲酸或对苯二甲酸);羟基羧酸(例如抗坏血酸、乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸);氨基酸(例如天冬氨酸或谷氨酸);苯甲酸;或有机磺酸(例如未取代的或被例如卤素取代的(C1-C4)-烷基或芳基磺酸)如甲烷磺酸或对甲苯磺酸)。
本公开的化合物可以其各种结晶形式、多晶型形式以及(无)水合形式提供。在这方面,本领域技术人员熟知的是,可以通过稍微改变纯化方法和/或从这类化合物的合成制备中使用的溶剂中分离来将化学化合物以这类形式中的任一种分离出来。
本公开还提供了一种合成根据式I的化合物或其药学上可接受的盐、溶剂化物或前药的方法。
关于下述合成方法的描述以及在用于制备起始材料的参考合成方法中,本领域技术人员将要理解的是,可以容易地选择所有建议的反应条件,包括溶剂的选择、反应气氛、反应温度、实验的持续时间和后处理工序。此外,本领域技术人员将要理解的是,分子的各种部分上存在的官能团必须与所采用的试剂和反应条件相容。
必要的起始材料可以通过有机化学的标准工序获得。结合以下代表性方法变型并且在下文的实施例内描述这类起始材料的制备。或者,必要的起始材料可以通过与在本领域技术人员的普通技能内的所示的那些工序类似的工序获得。进一步地,将了解的是,在化合物的合成期间、在下述方法中或在某些起始材料的合成期间,可能期望保护某些取代基以防止它们进行不期望的反应。本领域技术人员将容易地认识到何时需要这种保护以及可以如何将这类保护基团置于适当位置并在晚些时候去除。保护基团的实例描述于例如Theodora Green的Protective Groups in Organic Synthesis(出版商:John Wiley&Sons)中。可以通过本领域技术人员熟知的适合去除所讨论的保护基团的任何方便的方法去除保护基团,选择这类方法,以便在对分子中的别处的基团干扰最小的情况下实现保护基团的去除。因此,如果反应物包括诸如氨基、羧基或羟基的基团,则可能期望在本文提到的一些反应中将所述基团保护起来。
本公开的化合物可以通过例如国际专利公开号WO 2013/156780中描述的一般合成方法制备,所述专利公开以引用的方式并入本文。
在本公开的另一方面,提供了一种合成本公开的化合物(或其药学上可接受的盐、溶剂化物或前药)的方法,其中所述方法包括:
a)对于式I化合物,使式A化合物:
其中
R1和R2如上面关于式I定义,与合适的2-氨基吡啶衍生物反应;
或者,如果需要,使式B化合物
其中Hal为F、Cl、Br或I;且R1和R2如上面关于式I定义,与合适的吡啶基胍衍生物反应;并且,如果需要
b)则去除存在的任何保护基团,和/或形成其药学上可接受的盐、溶剂化物或前药。
式A或式B的化合物与2-氨基吡啶/吡啶基胍衍生物之间的偶联反应可以在存在合适的溶剂或溶剂混合物的情况下进行。本领域技术人员将能够容易地选择用于这个反应的合适溶剂或溶剂混合物。合适溶剂的实例包括醇、乙腈、卤化溶剂等。
另外,本领域技术人员将能够选择适当的反应条件以用于式A或式B的化合物的偶联反应。然而,典型地,反应将在无水条件下且在存在惰性气氛如氩气或氮气的情况下进行。反应也可以在例如80℃至180℃范围内的高温下进行例如20分钟至48小时的合适时间段。合适地,反应在例如80℃至180℃的微波加热下进行20分钟至1.5小时。
可以使用本领域技术人员公知的技术分离和纯化所得化合物。
合成本公开的化合物(或其药学上可接受的盐、溶剂化物或前药)的方法还可以包括:c)使式I化合物进行盐交换(特别是在化合物以不同盐形式的混合物形成的情况下)。
盐交换可以包括将化合物固定在合适的固体载体或树脂上,并用适当的酸洗脱化合物,产生式I化合物的盐。
用于合成本公开的化合物的特别合适的方法的实例如以下方案1所示。
方案1
其中一般反应条件是:(a)氯乙酮、EtOH,回流,o/n;(b)DMF-DMA,回流,o/n;(c)i.N,N'-双-Boc-S-甲基异硫脲、HgCl2、Et3N、DCM,0℃至室温,o/n;ii.TFA/DCM/H2O(18:9:1),50℃,o/n;(d)NaOH、2-甲氧基乙醇,微波,160-200℃,1小时;(e)吡啶-2-胺、Cs2CO3、Pd2(dba)3或Pd(OAc)2、4,5-双二苯基膦-9,9-二甲基氧杂蒽(xantphos)或BINAP、1,4-二噁烷,微波,160-200℃,1小时。
下文将参考以下非限制性实施例和附图描述本公开。
实施例
实施例1合成
总则
1H光谱在Bruker AVANCE III HD 500光谱仪上在298K下记录,并使用BrukerTopspin 3.2软件分析。报告1H NMR信号的化学位移值δ(ppm)、多重性(s=单峰,d=双重峰,t=三重峰,q=四重峰,dd=双重双重峰,dt=双重三重峰,td=三重双重峰,ddd=双重双重双重峰,m=多重峰,并且br=宽峰)、相对积分、耦合常数J(Hz)和赋值。高分辨率质谱在AB SCIEX TripleTOF 5600质谱仪(Concord,ON,Canada)上记录,并使用ESI进行所有样品的离子化。
一般合成工序A。向DMF-DMA(1.6当量)中添加氨基吡啶(1.0当量)。将反应混合物在回流下加热过夜,冷却至室温并在减压下浓缩。将残余物溶解于EtOH(升/摩尔所用氨基吡啶),并且添加1-氯丙酮(1.5当量)。将反应混合物在回流下加热过夜,冷却至室温且在减压下浓缩,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至EtOAc,除非另有说明)纯化,得到所需乙酮。
一般合成工序B。向DMF-DMA(5.0-10.0当量)中添加乙酮(1.0当量)。将反应混合物在回流下加热过夜,冷却至室温并过滤,用Et2O洗涤后,得到所需烯胺酮。
一般合成工序C。向2,4-二氯嘧啶(1.00当量)在PEG 400(1.67M于2,4-二氯嘧啶中)中的悬浮液中添加1-(乙烯氧基)丁烷(3.00当量)、TEA(1.00当量)和Pd(OAc)2(0.07当量)。将反应混合物用N2脱气十次,在80℃下加热2天,冷却至室温,用Et2O稀释并通过垫过滤。用Et2O洗涤固体,并且收集有机洗涤液,将其与滤液合并且用盐水洗涤。用Et2O(3×)萃取水性洗涤液,并且将有机萃取物与有机洗涤液和滤液的混合物合并,用盐水洗涤且在减压下浓缩。残余物通过快速柱色谱法(硅胶,石油醚渐变为石油醚:DCM=2:8)纯化,得到所需的4-(2-丁氧基乙烯基)嘧啶。
一般合成工序D。向4-(2-丁氧基乙烯基)嘧啶(1.00当量)在1,4-二噁烷和H2O的混合物(3:1,150mM于4-(2-丁氧基乙烯基)嘧啶中)中的溶液中添加NBS(1.00当量)。将反应混合物在室温下搅拌1小时,并且添加氨基吡啶(1.00当量)。将反应混合物在85℃下在N2下加热4小时,冷却至室温且在减压下浓缩。将残余物悬浮于EtOH中,使其在4℃下过夜且在冷却的同时过滤。将固体用冰冷的EtOH洗涤,干燥且用H2O进一步洗涤,得到所需咪唑并[1,2-a]吡啶的一部分。将有机洗涤液和水洗涤液合并且用DCM(3×)萃取,并且将有机萃取物合并且在减压下浓缩。残余物通过快速柱色谱法(硅胶,石油醚渐变为石油醚:EtOAc=1:4或DCM渐变为DCM:CH3OH=100:3)纯化,得到所需咪唑并[1,2-a]吡啶的第二部分。
一般合成工序E。向5-溴-2-硝基吡啶(1.0当量)在DMSO(2.5M于5-溴-2-硝基吡啶中)中的溶液中添加氮杂环(1.0-3.0当量)和TEA(3.0当量)。将反应混合物在120℃下加热过夜(除非另有说明),冷却至室温且经历如下所述的后处理,得到所需叔胺。
一般合成工序F。向硝基化合物(1.00当量)在CH3OH(50mM于硝基化合物中)中的悬浮液中添加10%Pd/C(0.01当量)。将反应混合物在室温下用H2鼓泡30分钟,在H2下搅拌过夜,并且通过垫过滤。将固体用CH3OH洗涤。将滤液和洗涤液合并且在减压下浓缩,得到所需伯胺;除非另有说明,否则通常不需要通过快速柱色谱法进一步纯化。
一般合成工序G。向在冰浴上的胺(1.0当量)、N,N'-双-Boc-S-甲基异硫脲(1.1-1.5当量)和TEA(3.5当量)在DCM(100mM胺)中的溶液中添加HgCl2(1.1-2.0当量)。将反应混合物在在冰浴上搅拌30分钟且在室温下过夜,并且通过垫过滤。将固体用DCM洗涤且将洗涤液与滤液合并且在减压下浓缩。残余物通过快速柱色谱法(硅胶,DCM渐变至DCM:CH3OH=94:6,除非另有说明)纯化,得到所需Boc保护的胍。
一般合成工序H。将Boc保护的胍(1.0当量)溶解在TFA(10当量)/DCM/H2O(18:9:1)的混合物中。将反应混合物在50℃下加热过夜且在减压下浓缩,得到所需三氟乙酸胍。
一般合成工序I。向烯胺酮(1.0当量)在2-甲氧基乙醇(0.25M于烯胺酮中)中的悬浮液中添加胍(1.0-1.5当量)。在使用胍盐的情况下,添加NaOH(1.0-2.4当量)。将反应混合物在微波辐射下在160-200℃下加热1小时,冷却至室温且在减压下浓缩。残余物通过FlashMaster Personal+色谱法或快速柱色谱法(硅胶,DCM渐变至含DCM:CH3OH:32%NH3的H2O=455:45:1)纯化,并且用冰冷的CH3OH(除非另有说明)洗涤,提供所需嘧啶。
一般合成工序J。向卤化物(1.00当量)在CH3CN(167mM于卤化物中)中的悬浮液中添加硼酸或硼酸酯(0.90-2.00当量)、Pd(dppf)Cl2·CH2Cl2或Ph(PPh3)4(0.05当量)和0.5MNa2CO3(1.40当量)。将反应混合物在微波辐射下在120-140℃下加热1小时(除非另有说明)。将反应混合物冷却至室温,浓缩且在含10%CH3OH的DCM和蒸馏的H2O之间分配。分离有机层且用10%CH3OH的DCM溶液(2×)萃取。将有机层和萃取物合并且浓缩,并且残余物通过快速柱色谱法(硅胶,DCM渐变至DCM:CH3OH=91:9,除非另有说明)纯化,提供所需加合物。
一般合成工序K。将卤化物(1.00当量)、胺(1.05-1.50当量)、Cs2CO3(2.00当量)、Pd2(dba)3或Pd(OAc)2(0.05当量)和4,5-双(二苯基膦)-9,9-二甲基呫吨(xantphos)(0.05当量)在1,4-二噁烷(100mM于卤化物中)中的悬浮液在微波辐射下在160-200℃下加热30-60分钟。将反应混合物冷却至室温,浓缩且在含10%CH3OH的DCM和蒸馏的H2O之间分配。分离有机层且用含10%CH3OH的DCM(2×)萃取。将有机层和萃取物合并且浓缩,并且残余物通过快速柱色谱法(硅胶,DCM渐变至DCM:CH3OH=93:7,除非另有说明)纯化,提供所需加合物。
一般合成工序L。向N-苯基磺化(氮杂)吲哚(1.0当量)在THF和CH3OH的混合物(1:1,25mM于N-苯基磺化(氮杂)吲哚中)中的悬浮液中添加LiOH(5.0当量)。将反应混合物在50℃下加热2小时,冷却至室温且用H2O稀释。将混合物用DCM(3×)萃取。将萃取物合并且在减压下浓缩,并且残余物通过快速柱色谱法(硅胶,DCM渐变至含DCM:CH3OH:32%NH3的H2O=455:45:1)纯化,提供所需N-未取代的(氮杂)吲哚。
1-(咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基吡啶(9.41g,100mmol)、DMF-DMA(21.2mL,160mmol)和1-氯丙酮(12.0mL,151mmol)经历一般合成工序A。棕色固体(7.16g,45%)。1H NMR(DMSO-d6)δ2.56(s,3H),7.26(td,1H,J 7.0&1.0),7.63(ddd,1H,J 9.0&7.0&1.5),7.82(d,1H,J 9.0),8.59(s,1H),9.51(dt,1H,J 7.0&1.0)。
1-(6-溴咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基-5-溴吡啶(17.3g,100mmol)、DMF-DMA(21.2mL,160mmol)和1-氯丙酮(12.0mL,151mmol)经历一般合成工序A。纯度为大约80%的橙色固体(8.80g,29%),其不经进一步纯化而用于下一步骤。1H NMR(CDCl3)δ2.61(s,3H),7.57(dd,1H,J 9.5&2.0),7.66(d,1H,J 9.5),8.31(s,1H),9.83(d,1H,J 1.5)。
1-(6-氟咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基-5-氟吡啶(11.3g,101mmol)、DMF-DMA(21.2mL,160mmol)和1-氯丙酮(12.0mL,151mmol)经历一般合成工序A。纯度为大约75%的棕色固体(5.94g,25%),其不经进一步纯化而用于下一步骤。1H NMR(CDCl3)δ2.61(s,3H),7.42(ddd,1H,J 10.0&7.5&2.5),7.74(d,1H,J 10.0&5.0),8.35(s,1H),9.65(dd,1H,J 9.5&2.5)。
1-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基-5-(三氟甲基)吡啶(16.3g,100mmol)、DMF-DMA(21.2mL,160mmol)和1-氯丙酮(12.0mL,151mmol)经历一般合成工序A。纯度为大约50%的棕色固体(8.00g,17%),其不经进一步纯化而用于下一步骤。1HNMR(CDCl3)δ2.65(s,3H),7.65(dd,1H,J 9.5&1.5),7.87(d,1H,J9.5),8.42(s,1H),10.02-10.05(m,1H)。
1-(6-甲基咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基-5-甲基吡啶(10.9g,101mmol)、DMF-DMA(21.2mL,160mmol)和1-氯丙酮(12.0mL,151mmol)经历一般合成工序A。浅棕色固体(5.36g,30%)。1HNMR(DMSO-d6)δ2.39(s,3H),2.55(s,3H),7.50(dd,1H,J 9.0&2.0),7.75(d,1H,J 9.0),8.56(s,1H),9.35-9.37(m,1H)。
1-(6-氯咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基-5-氯吡啶(12.9g,100mmol)、DMF-DMA(21.2mL,160mmol)和1-氯丙酮(12.0mL,151mmol)经历一般合成工序A。纯度为大约82%的棕色固体(7.38g,31%),其不经进一步纯化而用于下一步骤。1H NMR(CDCl3)δ2.61(s,3H),7.46(dd,1H,J 9.5&2.0),7.70(dd,1H,J 9.5&0.5),8.32(s,1H),9.73(dd,1H,J 2.0&0.5)。
1-(8-氟咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基-3-氟吡啶(11.3g,101mmol)、DMF-DMA(21.2mL,160mmol)和1-氯丙酮(12.0mL,151mmol)经历一般合成工序A。纯度为大约65%的棕色固体(9.18g,33%),其不经进一步纯化而用于下一步骤。1H NMR(CDCl3)δ2.63(s,3H),7.01(dt,1H,J 7.5&4.5),7.21(ddd,1H,J 9.0&8.0&1.0),8.34(s,1H),9.45(dd,1H,J 7.0&0.5)。
1-(8-溴咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基-3-溴吡啶(17.3g,100mmol)、DMF-DMA(21.2mL,160mmol)和1-氯丙酮(12.0mL,151mmol)经历一般合成工序A。纯度为大约40%的棕色固体(10.1g,17%),其不经进一步纯化而用于下一步骤。1H NMR(CDCl3)δ2.62(s,3H),6.96(t,1H,J 7.0),7.75(dd,1H,J 7.5&1.0),8.37(s,1H),9.63(dd,1H,J 7.0&1.0)。
1-(7-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基-4-(三氟甲基)吡啶(8.11g,50.0mmol)、DMF-DMA(10.7mL,80.5mmol)和1-氯丙酮(6.00mL,75.3mmol)经历一般合成工序A。纯度为大约64%的黄色固体(3.98g,22%),其不经进一步纯化而用于下一步骤。1H NMR(CDCl3)δ2.65(s,3H),7.25(dd,1H,J 7.0&1.5),8.06(s,1H),8.44(s,1H),9.76(d,1H,J 7.0)。
1-(2-甲基咪唑并[1,2-a]吡啶-3-基)乙-1-酮。向2-氨基吡啶(9.42g,100mmol)在1,2-二甲氧基乙烷(45mL)中的溶液中添加碳酸氢钠(8.40g,100mmol)和3-氯-2,4-戊二酮(16.9mL,150mmol)。将反应混合物在回流下加热3天,冷却至室温且在减压下浓缩,并且将残余物在蒸馏的H2O(300mL)和DCM(150mL)之间分配。分离有机层,并且将水层用2M NaOH调至pH 12且用DCM(3×150mL)萃取。将有机层和DCM萃取物合并且在减压下浓缩,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至EtOAc)纯化,得到为浅棕色固体的1-(2-甲基咪唑并[1,2-a]吡啶-3-基)乙-1-酮(15.2g,87%)。1H NMR(CDCl3)δ2.62(s,3H),2.80(s,3H),7.01(td,1H,J 6.5&1.0),7.45(ddd,1H,J 8.5&7.0&1.0),7.64(d,1H,J 9.0),9.74(d,1H,J7.0)。
1-(6-碘咪唑并[1,2-a]吡啶-3-基)乙-1-酮。使2-氨基-5-碘吡啶(22.0g,100mmol)、DMF-DMA(21.2mL,160mmol)和1-氯丙酮(12.0mL,151mmol)经历一般合成工序A。残余物通过快速柱色谱法(硅胶,DCM渐变至含2%CH3OH的DCM)纯化。纯度为大约80%的棕色固体(13.1g,37%),其不经进一步纯化而用于下一步骤。1H NMR(CDCl3)δ2.61(s,3H),7.55(d,1H,J 9.5),7.68(dd,1H,J 9.5&2.0),8.26(s,1H),9.93(dd,1H,J 1.0&0.5)。
(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮。使用一般合成工序B,使1-(咪唑并[1,2-a]吡啶-3-基)乙-1-酮(4.45g,27.8mmol)和DMF-DMA(18.5mL,139mmol)反应。米黄色固体(5.42g,91%)。1H NMR(CDCl3)δ2.99(br s,3H),3.10(br s,3H),5.67(d,1H,J12.5),7.16(td,1H,J 7.0&1.0),7.36(ddd,1H,J 9.0&7.0&1.5),7.68(dt,1H,J 9.0&1.0),7.77(d,1H,J 12.5),8.21(s,1H),9.80(dt,1H,J 7.0&1.0)。
(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮。使用一般合成工序B,使1-(6-溴咪唑并[1,2-a]吡啶-3-基)乙-1-酮(5.25g,约80%纯度,17.6mmol)和DMF-DMA(16.7mL,126mmol)反应。浅棕色固体(4.98g,96%)。1H NMR(CDCl3)δ2.95(br s,3H),3.16(br s,3H),5.64(d,1H,J 12.5),7.42(dd,1H,J 9.5&1.5),7.57(d,1H,J 9.5),7.78(d,1H,J 12.5),8.17(s,1H),10.01(d,1H,J 1.5)。
(E)-3-(二甲基氨基)-1-(6-氟咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮。使用一般合成工序B,使1-(6-氟咪唑并[1,2-a]吡啶-3-基)乙-1-酮(5.94g,约75%纯度,25.0mmol)和DMF-DMA(22.1mL,166mmol)反应。黑色固体(4.88g,84%)。1H NMR(CDCl3)δ2.94(br s,3H),3.14(br s,3H),5.63(d,1H,J 12.5),7.26(ddd,1H,J 10.0&7.5&2.5),7.63(dd,1H,J 10.0&5.0),7.76(d,1H,J 12.5),8.20(s,1H),9.80(dd,1H,J 5.0&2.5)。
(E)-3-(二甲基氨基)-1-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1- 酮。使用一般合成工序B,使1-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)乙-1-酮(8.00g,约50%纯度,17.5mmol)和DMF-DMA(23.4mL,176mmol)反应。棕色固体(4.90g,98%)。1H NMR(CDCl3)δ2.97(br s,3H),3.18(br s,3H),5.66(d,1H,J 12.0),7.59(dd,1H,J 9.0&1.5),7.70(d,1H,J 9.0),7.81(d,1H,J 12.5),8.26(s,1H),10.23-10.26(m,1H)。
(E)-3-(二甲基氨基)-1-(6-甲基咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮。使用一般合成工序B,使1-(6-甲基咪唑并[1,2-a]吡啶-3-基)乙-1-酮(4.69g,26.9mmol)和DMF-DMA(17.9mL,135mmol)反应。棕色固体(5.73g,93%)。1H NMR(CDCl3)δ2.38(d,3H,J 0.5),3.50(app br s,6H),5.66(d,1H,J 12.5),7.21(dd,1H,J 9.0&1.5),7.58(d,1H,J 9.0),7.75(d,1H,J 12.0),8.16(s,1H),9.63-9.65(m,1H)。
(E)-1-(6-氯咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮。使用一般合成工序B,使1-(6-氯咪唑并[1,2-a]吡啶-3-基)乙-1-酮(7.38g,约82%纯度,31.1mmol)和DMF-DMA(25.2mL,190mmol)反应。棕色固体(6.28g,81%)。1H NMR(CDCl3)δ2.96(br s,3H),3.16(br s,3H),5.64(d,1H,J 12.5),7.32(dd,1H,J 9.5&2.0),7.62(dd,1H,J9.5&1.0),7.78(d,1H,J 12.5),8.19(s,1H),9.91(dd,1H,J 2.0&1.0)。
(E)-3-(二甲基氨基)-1-(8-氟咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮。使用一般合成工序B,使1-(8-氟咪唑并[1,2-a]吡啶-3-基)乙-1-酮(9.18g,约65%纯度,33.5mmol)和DMF-DMA(22.3mL,168mmol)反应。棕色固体(7.01g,90%)。1H NMR(CDCl3)δ2.94(br s,3H),3.15(br s,3H),5.65(d,1H,J 13.0),6.87(dd,1H,J 7.5&5.0),7.05(ddd,1H,J10.0&7.5&1.0),7.77(d,1H,J 12.5),8.18(s,1H),9.59(dd,1H,J 7.0&1.0)。
(E)-1-(8-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮。使用一般合成工序B,使1-(8-溴咪唑并[1,2-a]吡啶-3-基)乙-1-酮(10.1g,约40%纯度,16.9mmol)和DMF-DMA(11.2mL,84.3mmol)反应。棕色固体(3.82g,77%)。1H NMR(CDCl3)δ2.96(br s,3H),3.15(br s,3H),5.64(d,1H,J 12.5),6.84(t,1H,J 7.0),7.60(d,1H,J7.5),7.77(d,1H,J 12.5),8.21(s,1H),9.79(d,1H,J 7.0)。
(E)-3-(二甲基氨基)-1-(7-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1- 酮。使用一般合成工序B,使1-(7-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)乙-1-酮(3.98g,约64%纯度,11.2mmol)和DMF-DMA(7.50mL,56.4mmol)反应。金色固体(3.14g,99%)。1H NMR(CDCl3)δ2.97(br s,3H),3.18(br s,3H),5.67(d,1H,J 12.5),7.13(dd,1H,J 7.5&1.5),7.81(d,1H,J 12.0),7.98(app s,1H),8.29(s,1H),9.92(d,1H,J 7.5)。
(E)-3-(二甲基氨基)-1-(2-甲基咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮。使用一般合成工序B,使1-(2-甲基咪唑并[1,2-a]吡啶-3-基)乙-1-酮(8.71g,50.0mmol)和DMF-DMA(33.2mL,250mmol)反应。棕色固体(9.95g,87%)。1H NMR(CDCl3)δ2.76(s,3H),2.97(brs,3H),3.11(br s,3H),5.56(d,1H,J 12.5),6.88(t,1H,J 6.5),7.29(dd,1H,J 8.5&2.0),7.55(d,1H,J 9.0),7.78(d,1H,J 12.0),9.65(d,1H,J 6.5)。
(E)-3-(二甲基氨基)-1-(6-碘咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮。使用一般合成工序B,使1-(6-碘咪唑并[1,2-a]吡啶-3-基)乙-1-酮(10.8g,80%纯度,30.2mmol)和DMF-DMA(20.1mL,151mmol)反应。深棕色固体(9.41g,91%)。1H NMR(CDCl3)δ2.95(br s,3H),3.15(br s,3H),5.63(d,1H,J 12.0),7.45(dd,1H,J 9.5&0.5),7.52(dd,1H,J 9.5&1.5),7.77(d,1H,J 12.0),8.11(s,1H),10.10(dd,1H,J 1.5&0.5)。
(E)-4-(2-丁氧基乙烯基)-2-氯-5-氟嘧啶。使用一般合成工序C,使2,4-二氯-5-氟嘧啶(16.7g,100mmol)和1-(乙烯氧基)丁烷(38.8mL,300mmol)偶联。淡黄色油(14.8g,64%)。1H NMR(CDCl3)δ0.96(t,3H,J 7.5),1.41-1.49(m,2H),1.69-1.77(m,2H),4.00(t,2H,J 6.5),5.90(dd,1H,J 12.5&0.5),8.00(d,1H,J 12.5),8.21(d,1H,J 2.0)。
(E)-4-(2-丁氧基乙烯基)-2-氯-5-甲基嘧啶。使用一般合成工序C,使2,4-二氯-5-甲基嘧啶(16.3g,100mmol)和1-(乙烯氧基)丁烷(38.8mL,300mmol)偶联。棕色粘性固体(6.81g,30%)。1H NMR(CDCl3)δ0.95(t,3H,J 7.5),1.39-1.48(m,2H),1.67-1.75(m,2H),2.16(s,3H),3.99(t,2H,J 6.5),5.79(dd,1H,J 12.0&1.5),7.96(d,1H,J 12.0),8.14(s,1H)。
3-(2-氯-5-氟嘧啶-4-基)咪唑并[1,2-a]吡啶。使(E)-4-(2-丁氧基乙烯基)-2-氯-5-氟嘧啶(8.07g,35.0mmol)、NBS(6.23g,35.0mmol)和2-氨基吡啶(3.29g,35.0mmol)经历一般合成工序D。米黄色固体(3.49g,40%)。1H NMR(DMSO-d6)δ7.36(t,1H,J 7.0),7.66(ddd,1H,J 8.5&7.0&1.0),7.88(d,1H,J 8.5),8.53(d,1H,J 4.0),8.84(d,1H,J 3.5),9.76(d,1H,J 7.0)。
3-(2-氯-5-氟嘧啶-4-基)-6-氟咪唑并[1,2-a]吡啶。使(E)-4-(2-丁氧基乙烯基)-2-氯-5-氟嘧啶(2.21g,9.58mmol)、NBS(1.71g,9.61mmol)和2-氨基-5-氟吡啶(1.08g,9.63mmol)经历一般合成工序D。灰色固体(2.00g,78%)。1H NMR(DMSO-d6)δ7.76(ddd,1H,J10.0&7.5&2.5),7.96(dd,1H,J 10.0&5.5),8.54(d,1H,J 4.0),8.88(d,1H,J 3.5),9.75(dd,1H,J 5.5&2.5)。
3-(2-氯-5-氟嘧啶-4-基)-6-溴咪唑并[1,2-a]吡啶。使(E)-4-(2-丁氧基乙烯基)-2-氯-5-氟嘧啶(5.55g,24.1mmol)、NBS(4.29g,24.1mmol)和2-氨基-5-溴吡啶(4.17g,24.1mmol)经历一般合成工序D。米黄色固体(2.05g,26%)。1H NMR(CDCl3)δ7.63(d,1H,J9.5),7.78(d,1H,J 9.5),8.51(d,1H,J 3.0),8.58(d,1H,J 3.5),10.18(s,1H)。
3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶。使用一般合成工序J,通过3-(2-氯-5-氟嘧啶-4-基)-6-溴咪唑并[1,2-a]吡啶(988mg,3.02mmol)与苯基硼酸(331mg,2.71mmol)的反应制备。白色固体(480mg,54%)。1H NMR(DMSO-d6)δ7.55-7.62(m,3H),7.76(d,2H,J 7.5),7.99(app s,1H),8.00(d,1H,J 2.0),8.57(d,1H,J 4.0),8.89(d,1H,J3.5),10.11(s,1H)。
3-(2-氯-5-氟嘧啶-4-基)-6-甲基咪唑并[1,2-a]吡啶。使(E)-4-(2-丁氧基乙烯基)-2-氯-5-氟嘧啶(2.21g,9.58mmol)、NBS(1.71g,9.61mmol)和2-氨基-5-甲基吡啶(1.04g,9.61mmol)经历一般合成工序D。灰色固体(1.81g,72%)。1H NMR(DMSO-d6)δ2.46(s,3H),7.74(dd,1H,J 9.0&1.5),7.89(d,1H,J 9.0),8.68(d,1H,J 3.5),8.93(d,1H,J3.0),9.59(s,1H)。
3-(2-氯-5-氟嘧啶-4-基)-6-(三氟甲基)咪唑并[1,2-a]吡啶。使(E)-4-(2-丁氧基乙烯基)-2-氯-5-氟嘧啶(2.21g,9.58mmol)、NBS(1.71g,9.61mmol)和2-氨基-5-(三氟甲基)吡啶(1.55g,9.56mmol)经历一般合成工序D。米黄色固体(1.79g,59%)。1H NMR(DMSO-d6)δ7.90(dd,1H,J 9.5&1.5),8.08(d,1H,J 9.5),8.64(d,1H,J 3.5),8.94(d,1H,J 3.5),10.21(s,1H)。
3-(2-氯-5-甲基嘧啶-4-基)咪唑并[1,2-a]吡啶。使(E)-4-(2-丁氧基乙烯基)-2-氯-5-甲基嘧啶(4.53g,20.0mmol)、NBS(3.56g,20.0mmol)和2-氨基吡啶(1.88g,20.0mmol)经历一般合成工序D。米黄色固体(2.54g,50%)。1H NMR(DMSO-d6)δ2.52(s,3H),7.24(t,1H,J 7.0),7.57(t,1H,J 8.0),7.82(d,1H,J 9.0),8.44(s,1H),8.67(s,1H),9.59(d,1H,J7.0)。
4-(6-硝基吡啶-3-基)哌嗪-1-羧酸叔丁酯。使5-溴-2-硝基吡啶(4.06g,20.0mmol)和哌嗪-1-羧酸叔丁酯(4.47g,24.0mmol)经历一般合成工序E。将反应混合物在70℃下加热3天,用H2O(20mL)和EtOAc(20mL)的混合物稀释,冷却至室温且使其在4℃下过夜。将如此形成的沉淀物过滤且用H2O(20mL)洗涤,得到为黄色固体的4-(6-硝基吡啶-3-基)哌嗪-1-羧酸叔丁酯(5.70g,92%)。1H NMR(CDCl3)δ1.46(s,9H),3.44(t,4H,J 5.0),3.62(t,4H,J 5.0),7.19(dd,1H,J 9.5&3.0),8.10(d,1H,J 3.0),8.14(d,1H,J 9.0)。
1-甲基-4-(6-硝基吡啶-3-基)哌嗪。使5-溴-2-硝基吡啶(10.2g,50.2mmol)和1-甲基哌嗪(6.66mL,60.0mmol)经历一般合成工序E。将反应混合物在减压下浓缩,并且将残余物用EtOAc(60mL)研磨且过滤(滤液A)。将固体用EtOAc(100mL)洗涤,干燥且溶解在H2O(100mL)中。将溶液用饱和Na2CO3水溶液调至pH 11-12,并且将如此形成的沉淀物过滤(滤液B),得到为深棕色固体的1-甲基-4-(6-硝基吡啶-3-基)哌嗪的一部分(4.44g)。将滤液A和B合并且用DCM(3×100mL)萃取。将有机萃取物合并,经Na2SO4干燥且在减压下浓缩。将残余物用EtOAc结晶,得到为深棕色晶体的1-甲基-4-(6-硝基吡啶-3-基)哌嗪的第二部分(3.66g)。总收率:8.10g,72%。1H NMR(CDCl3)δ2.35(s,3H),2.56(t,4H,J 5.0),3.45(t,4H,J 5.0),7.18(dd,1H,J 9.0&3.0),8.11(d,1H,J 3.0),8.14(d,1H,J 9.5)。
1-乙基-4-(6-硝基吡啶-3-基)哌嗪。使5-溴-2-硝基吡啶(7.76g,38.2mmol)和1-乙基哌嗪(4.58g,40.1mmol)经历一般合成工序E。将反应混合物在90℃下加热过夜,冷却至室温,在减压下浓缩,并且将残余物用EtOAc(60mL)研磨且过滤。将固体用EtOAc(100mL)洗涤,干燥且通过快速柱色谱法(硅胶,DCM渐变至DCM:CH3OH=9:1)纯化,得到为橙色固体的1-乙基-4-(6-硝基吡啶-3-基)哌嗪(6.79g,75%)。1H NMR(CDCl3)δ1.14(t,3H,J 7.0),2.49(q,2H,J 7.0),2.62(t,4H,J5.0),3.48(t,4H,J 5.0),7.19(dd,1H,J 9.0&3.0),8.13(d,1H,J 3.0),8.16(d,1H,J 9.0)。
1-(4-(6-硝基吡啶-3-基)哌嗪-1-基)乙-1-酮。使5-溴-2-硝基吡啶(5.00g,24.6mmol)和1-(哌嗪-1-基)乙-1-酮(5.00g,39.0mmol)经历一般合成工序E。将反应混合物用EtOAc(50mL)稀释,并且将如此形成的沉淀物过滤且用EtOAc(10mL)和H2O(30mL)洗涤,得到为黄色固体的1-(4-(6-硝基吡啶-3-基)哌嗪-1-基)乙-1-酮的一部分(2.77g)。将滤液和洗涤液合并且用DCM(3×100mL)萃取。将有机萃取物合并,经Na2SO4干燥且在减压下浓缩。残余物通过FlashMaster Personal+色谱法(硅胶,DCM渐变至DCM:CH3OH=94:6)纯化,得到为黄色固体的1-(4-(6-硝基吡啶-3-基)哌嗪-1-基)乙-1-酮的第二部分(2.89g)。总收率:5.66g,92%。1H NMR(CDCl3)δ2.16(s,3H),3.47(t,2H,J 5.5),3.52(t,2H,J 5.5),3.71(t,2H,J 5.5),3.83(t,2H,J 5.5),7.22(dd,1H,J 9.0&3.0),8.13(d,1H,J 3.0),8.17(d,1H,J9.0)。
1-(甲基磺酰基)-4-(6-硝基吡啶-3-基)哌嗪。使5-溴-2-硝基吡啶(2.03g,10.0mmol)和1-(甲磺酰基)哌嗪(1.97g,12.0mmol)经历一般合成工序E。使反应混合物在4℃下过夜且过滤,并且将固体用H2O(50mL)洗涤,过滤且通过快速柱色谱法(硅胶,DCM渐变至DCM:CH3OH=95:5)纯化,得到为黄色固体的1-(甲基磺酰基)-4-(6-硝基吡啶-3-基)哌嗪(2.29g,80%)。1H NMR(CDCl3)δ2.93(s,3H),3.26(t,4H,J 5.0),3.64(t,4H,J 5.0),7.54(dd,1H,J 9.5&2.5),8.20(d,1H,J9.5),9.30(d,1H,J 2.5)。
4-(6-硝基吡啶-3-基)吗啉。使5-溴-2-硝基吡啶(2.00g,9.85mmol)和吗啉(1.30mL,14.9mmol)经历一般合成工序E。将反应混合物在减压下浓缩,并且将残余物用EtOAc(75mL)研磨且过滤,得到为黄色固体的4-(6-硝基吡啶-3-基)吗啉(2.06g,100%)。1HNMR(CDCl3)δ3.41(t,4H,J 5.0),3.89(t,4H,J 5.0),7.22(dd,1H,J 9.0&3.0),8.13(d,1H,J 3.0),8.18(d,1H,J 9.0)。
2-硝基-5-(哌啶-1-基)吡啶。使5-溴-2-硝基吡啶(5.07g,25.0mmol)和哌啶(7.40mL,74.9mmol)经历一般合成工序E。将反应混合物在120℃下加热2天,冷却至室温且在减压下浓缩,并且将残余物用EtOAc(300mL)研磨,过滤且用EtOAc(200mL)洗涤。将滤液和洗涤液合并且在减压下浓缩,并且将残余物用H2O(400mL)研磨且过滤。将固体用H2O(100mL)洗涤,干燥且通过快速柱色谱法(硅胶,DCM渐变至DCM:CH3OH=98:2)纯化,得到为黄色固体的2-硝基-5-(哌啶-1-基)吡啶(4.06g,78%)。1H NMR(CDCl3)δ1.69(app s,6H),3.45(t,4H,J 5.0),7.13(dd,1H,J 9.0&2.5),8.07(d,1H,J 2.5),8.10(d,1H,J9.0)。
N,N-二甲基-1-(6-硝基吡啶-3-基)哌啶-4-胺。使5-溴-2-硝基吡啶(2.03g,10.0mmol)和N,N-二甲基哌啶-4-胺(1.58g,12.3mmol)经历一般合成工序E。将反应混合物在减压下浓缩,并且将残余物用EtOAc(100mL)研磨且过滤。将固体用EtOAc(100mL)洗涤,干燥且通过快速柱色谱法(硅胶,DCM渐变至DCM:CH3OH=9:1)纯化,得到为黄色固体的N,N-二甲基-1-(6-硝基吡啶-3-基)哌啶-4-胺(2.07g,83%)。1HNMR(CDCl3)δ1.64(d,2H,J 12.0),2.00(d,2H,J 13.0),2.33(s,6H),2.40-2.48(m,1H),3.05(t,2H,J 12.0),3.97(d,2H,J13.0),7.19(d,1H,J 9.0),8.12-8.17(m,2H)。
1-(6-硝基吡啶-3-基)-1,4-二氮杂环庚烷。使5-溴-2-硝基吡啶(10.2g,50.2mmol)和高哌嗪(5.03g,50.2mmol)经历一般合成工序E。将反应混合物在减压下浓缩,并且将残余物溶解在饱和Na2CO3水溶液(100mL)中。将所得溶液用2M NaOH调至pH 14且用DCM(6×100mL)萃取。将有机萃取物合并且在减压下浓缩,得到为橙色固体的1-(6-硝基吡啶-3-基)-1,4-二氮杂环庚烷(5.67g,51%)。1H NMR(CDCl3)δ1.90-1.96(m,2H),2.85(t,2H,J 6.0),3.07(t,2H,J 5.5),3.64(t,2H,J5.5),3.71(t,2H,J 6.0),7.01(dd,1H,J 9.5&3.0),7.98(d,1H,J 3.0),8.14(d,1H,J 9.0)(一个质子信号(NH)未观察到)。
1-(4-(6-硝基吡啶-3-基)-1,4-二氮杂环庚烷-1-基)乙-1-酮。向在冰浴上的1-(6-硝基吡啶-3-基)-1,4-二氮杂环庚烷(3.33g,15.0mmol)和TEA(2.09mL,15.0mmol)在CHCl3(50mL)中的溶液中滴加乙酰氯(2.13mL,30.0mmol)。将反应混合物在室温下搅拌72小时并且在减压下浓缩。残余物通过快速柱色谱法(硅胶,DCM渐变至DCM:CH3OH=95:5)纯化,得到为黄色固体的1-(4-(6-硝基吡啶-3-基)-1,4-二氮杂环庚烷-1-基)乙-1-酮(3.47g,88%)。1H NMR(CDCl3)(化合物作为以大约4.5:5.5比率的两种旋转异构体存在。主要旋转异构体指定为#且次要旋转异构体指定为*。)δ1.94-1.98(m,2H),1.98*(s,1.35H),2.02#(s,1.65H),3.42#(t,1.1H,J 6.5),3.43*(t,0.9H,J 6.5),3.61-3.66#,*,*(m,2.9H),3.69#(t,1.1H,J 6.0),3.75#(t,1.1H,J 5.5),3.76*(t,0.9H,J 5.5),7.02#(dd,0.55H,J 9.0&3.0),7.03*(dd,0.45H,J 8.5&3.0),7.92#(d,0.55H,J 3.0),7.93*(d,0.45H,J 3.0),8.06#(d,0.55H,J 9.5),8.08*(d,0.45H,J 9.0)。
4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯。根据一般合成工序F,使4-(6-硝基吡啶-3-基)哌嗪-1-羧酸叔丁酯(4.78g,15.5mmol)还原。棕色固体(3.99g,92%)。1H NMR(CDCl3)δ1.46(s,9H),2.93(app s,4H),3.55(t,4H,J 5.0),4.24(br s,2H),6.47(d,1H,J9.0),7.15(dd,1H,J 9.0&2.5),7.75(d,1H,J 2.5)。
5-(4-甲基哌嗪-1-基)吡啶-2-胺。根据一般合成工序F,使1-甲基-4-(6-硝基吡啶-3-基)哌嗪(4.44g,20.0mmol)还原。灰色固体(3.84g,100%)。1H NMR(CDCl3)δ2.33(s,3H),2.56(t,4H,J 5.0),3.05(t,4H,J5.0),4.17(br s,2H),6.47(d,1H,J 9.0),7.16(dd,1H,J 8.5&3.0),7.77(d,1H,J 2.5)。
5-(4-乙基哌嗪-1-基)吡啶-2-胺。根据一般合成工序F,使1-乙基-4-(6-硝基吡啶-3-基)哌嗪(6.79g,28.7mmol)还原,并且残余物通过快速柱色谱法(硅胶,DCM渐变至含DCM:CH3OH:32%NH3的H2O=450:50:1)纯化。紫色固体(4.87g,82%)。1H NMR(CDCl3)δ1.11(t,3H,J 7.5),2.47(q,2H,J 7.5),2.60(t,4H,J 4.5),3.06(t,4H,J 4.5),4.17(br s,2H),6.47(d,1H,J 8.5),7.17(dd,1H,J 8.5&2.0),7.77(d,1H,J 2.0)。
1-(4-(6-氨基吡啶-3-基)哌嗪-1-基)乙-1-酮。根据一般合成工序F,使1-(4-(6-硝基吡啶-3-基)哌嗪-1-基)乙-1-酮(700mg,2.80mmol)还原。紫色固体(616mg,100%)。1HNMR(CDCl3)δ2.13(s,3H),2.97(t,2H,J 5.0),3.01(t,2H,J 5.0),3.60(t,2H,J 5.0),3.76(t,2H,J 5.0),4.22(br s,2H),6.49(d,1H,J 8.5),7.17(dd,1H,J 8.5&3.0),7.78(d,1H,J3.0)。
5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-胺。根据一般合成工序F,使1-(甲基磺酰基)-4-(6-硝基吡啶-3-基)哌嗪(1.31g,4.58mmol)还原。黄色固体(1.17g,100%)。1H NMR(CDCl3)δ2.83(s,3H),3.11(t,4H,J5.0),3.38(t,4H,J 5.0),4.24(s,2H),6.49(d,1H,J8.5),7.17(dd,1H,J8.5&2.5),7.79(d,1H,J 2.5)。
5-吗啉代吡啶-2-胺。根据一般合成工序F,使4-(6-硝基吡啶-3-基)吗啉(4.60g,22.0mmol)还原。白色固体(3.94g,100%)。1H NMR(CDCl3)δ2.99(t,4H,J 4.5),3.83(t,4H,J4.5),4.23(br s,2H),6.47(d,1H,J 9.0),7.13(dd,1H,J 9.0&3.0),7.75(d,1H,J 2.5)。
5-(哌啶-1-基)吡啶-2-胺。根据一般合成工序F,使2-硝基-5-(哌啶-1-基)吡啶(3.70g,17.8mmol)还原。白色固体(3.10g,98%)。1H NMR(CDCl3)δ1.52-1.54(m,2H),1.69-1.73(m,4H),2.97(t,4H,J 5.5),4.15(s,2H),6.47(d,1H,J 9.0),7.18(dd,1H,J 9.0&3.0),7.77(d,1H,J3.0)。
5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-胺。根据一般合成工序F,使N,N-二甲基-1-(6-硝基吡啶-3-基)哌啶-4-胺(2.00g,7.99mmol)还原。白色固体(1.66g,94%),其不经进一步纯化和表征而用于下一步骤。
1-(4-(6-氨基吡啶-3-基)-1,4-二氮杂环庚烷-1-基)乙-1-酮。根据一般合成工序F,使1-(4-(6-硝基吡啶-3-基)-1,4-二氮杂环庚烷-1-基)乙-1-酮(3.47g,13.1mmol)还原。淡棕色固体(3.08g,100%)。1H NMR(CDCl3)(化合物作为以大约4.5:5.5比率的两种旋转异构体存在。主要旋转异构体指定为#且次要旋转异构体指定为*。)δ1.90-1.96(m,2H),1.98*(s,1.35H),2.06#(s,1.65H),3.35#(t,1.1H,J 6.0),3.40*(t,0.9H,J6.0),3.41-3.45#,*(m,2H),3.46#(t,1.1H,J 6.0),3.50-3.53*(m,0.9H),3.55-3.59*(m,0.9H),3.68-3.71#(m,1.1H),6.45#,*(d,0.45H,J 9.0;d,0.55H J 9.0),6.94#(app t,0.55H,J 8.5),6.95*(appt,0.45H,J 8.5),7.59*(d,0.45H,J 2.0),7.60#(d,0.55H,J 2.5)(两个质子信号(NH2)未观察到)。
2-(2,3-双(叔-丁氧基羰基)胍基)吡啶。使用一般合成工序G,在存在HgCl2(10.4g,38.3mmol)的情况下,使吡啶-2-胺(2.78g,29.5mmol)和N,N’-双-Boc-S-甲基异硫脲(11.2g,38.6mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至石油醚:EtOAc=9:1)纯化且用DCM和己烷进一步结晶。白色固体(4.18g,42%)。1H NMR(CDCl3)δ1.52(s,18H),7.01(dd,1H,J 7.0&5.0),7.70(t,1H,J 7.0),8.29(d,1H,J 4.0),8.37(app brs,1H),10.89(br s,1H),11.53(br s,1H)。
2-(2,3-双(叔-丁氧基羰基)胍基)吡嗪。使用一般合成工序G,在存在HgCl2(1.63g,6.00mmol)的情况下,使吡嗪-2-胺(476mg,5.00mmol)和N,N’-双-Boc-S-甲基异硫脲(1.75g,6.03mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至石油醚:EtOAc=6:4)纯化。米黄色固体(1.25g,74%)。1H NMR(CDCl3)δ1.50(s,9H),1.52(s,9H),8.26(s,1H),8.32(s,1H),9.74(s,1H),10.85(br s,1H),11.49(br s,1H)。
2-(2,3-双(叔-丁氧基羰基)胍基)-5-氟吡啶。使用一般合成工序G,在存在HgCl2(5.97g,22.0mmol)的情况下,使5-氟吡啶-2-胺(2.24g,20.0mmol)和N,N’-双-Boc-S-甲基异硫脲(6.38g,22.0mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至石油醚:DCM=1:9)纯化。白色固体(4.83g,68%)。1H NMR(CDCl3)δ1.52(s,9H),1.54(s,9H),7.44(td,1H,J 8.0&2.0),8.15(d,1H,J 2.0),8.42(d,1H,J 5.5),10.90(br s,1H),11.51(s,1H)。
2-(2,3-双(叔-丁氧基羰基)胍基)-5-氯吡啶。使用一般合成工序G,在存在HgCl2(5.97g,22.0mmol)的情况下,使5-氯吡啶-2-胺(2.57g,20.0mmol)和N,N’-双-Boc-S-甲基异硫脲(6.39g,22.0mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至石油醚:DCM=1:9)纯化。白色固体(3.25g,44%)。1H NMR(CDCl3)δ1.53(s,9H),1.54(s,9H),7.67(d,1H,J 9.0),8.24(s,1H),8.39(d,1H,J 8.5),10.92(br s,1H),11.51(s,1H)。
2-(2,3-双(叔-丁氧基羰基)胍基)-5-溴吡啶。使用一般合成工序G,在存在HgCl2(17.7g,65.2mmol)的情况下,使5-溴吡啶-2-胺(8.65g,50.0mmol)和N,N’-双-Boc-S-甲基异硫脲(18.9g,65.1mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至石油醚:DCM=1:9)纯化。白色固体(8.32g,40%)。1H NMR(CDCl3)δ1.53(s,9H),1.54(s,9H),7.80(dd,1H,J 9.0&2.0),8.34(d,1H,J 2.0),8.35(d,1H,J 9.0),10.91(br s,1H),11.50(s,1H)。
2-(2,3-双(叔-丁氧基羰基)胍基)-5-碘吡啶。使用一般合成工序G,在存在HgCl2(5.97g,22.0mmol)的情况下,使5-碘吡啶-2-胺(4.40g,20.0mmol)和N,N’-双-Boc-S-甲基异硫脲(6.39g,22.0mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至石油醚:DCM=1:9)纯化。白色固体(3.37g,36%)。1H NMR(CDCl3)δ1.52(s,9H),1.53(s,9H),7.96(d,1H,J 9.0),8.25(d,1H,J 8.0),8.48(s,1H),10.88(br s,1H),11.50(s,1H)。
2-(2,3-双(叔-丁氧基羰基)胍基)-5-甲基吡啶。使用一般合成工序G,在存在HgCl2(5.97g,22.0mmol)的情况下,使5-甲基吡啶-2-胺(2.16g,20.0mmol)和N,N’-双-Boc-S-甲基异硫脲(6.39g,22.0mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚经DCM渐变至DCM:CH3OH=97:3)纯化。白色固体(3.03g,43%)。1H NMR(CDCl3)δ1.52(s,9H),1.53(s,9H),2.28(s,3H),7.51(d,1H,J 8.5),8.11(s,1H),8.24(br s,1H),10.81(br s,1H),11.53(s,1H)。
4-(6-(2,3-双(叔-丁氧基羰基)胍基)吡啶-3-基)哌嗪-1-羧酸叔丁酯。使用一般合成工序G,在存在HgCl2(4.79g,17.6mmol)的情况下,使4-(6-氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯(3.78g,13.6mmol)和N,N'-双-Boc-S-甲基异硫脲(5.13g,17.7mmol)反应。白色固体(4.25g,60%)。1H NMR(CDCl3)δ1.48(s,9H),1.52(s,18H),3.09(t,4H,J 4.5),3.58(t,4H,J 5.0),7.28(dd,1H,J 9.0&3.0),7.96(d,1H,J 3.0),8.22(app br s,1H),10.75(brs,1H),11.51(br s,1H)。
1-甲基-4-(6-(2,3-双(叔-丁氧基羰基)胍基)吡啶-3-基)哌嗪。使用一般合成工序G,在存在HgCl2(11.6g,42.7mmol)的情况下,使5-(4-甲基哌嗪-1-基)吡啶-2-胺(5.49g,28.6mmol)和N,N’-双-Boc-S-甲基异硫脲(12.4g,42.7mmol)反应。米黄色固体(8.06g,65%)。1H NMR(CDCl3)δ1.51(s,18H),2.34(s,3H),2.57(t,4H,J 5.0),3.17(t,4H,J5.0),7.26(dd,1H,J 8.5&3.0),7.96(d,1H,J 2.5),8.20(br d,1H,J 8.0),10.70(br s,1H),11.51(br s,1H)。
1-乙基-4-(6-(2,3-双(叔-丁氧基羰基)胍基)吡啶-3-基)哌嗪。使用一般合成工序G,在存在HgCl2(5.13g,18.9mmol)的情况下,使5-(4-乙基哌嗪-1-基)吡啶-2-胺(3.00g,14.5mmol)和N,N’-双-Boc-S-甲基异硫脲(5.49g,18.9mmol)反应。淡绿色泡沫(6.27g,96%)。1H NMR(CDCl3)δ1.14(t,3H,J 7.0),1.52(s,9H),1.53(s,9H),2.51(q,2H,J7.0),2.64(t,4H,J 4.5),3.21(t,4H,J 4.5),7.28(dd,1H,J 9.0&2.5),7.98(s,1H),8.18(d,1H,J 6.5),10.72(s,1H),11.52(s,1H)。
1-乙酰基-4-(6-(2,3-双(叔-丁氧基羰基)胍基)吡啶-3-基)哌嗪。使用一般合成工序G,在存在HgCl2(5.45g,20.1mmol)的情况下,使1-(4-(6-氨基吡啶-3-基)哌嗪-1-基)乙-1-酮(2.21g,10.0mmol)和N,N'-双-Boc-S-甲基异硫脲(3.50g,12.0mmol)反应。白色固体(3.82g,82%)。1H NMR(CDCl3)δ1.55(s,9H),1.56(s,9H),2.15(s,3H),3.19(t,2H,J5.0),3.25(t,2H,J 5.0),3.64(t,2H,J 5.0),3.78(t,2H,J 5.0),7.08(d,1H,J 8.5),7.32(dd,1H,J 9.0&3.0),8.03(d,1H,J 3.0),11.27(br s,1H),11.74(br s,1H)。
1-(甲基磺酰基)-4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)哌嗪。使用一般合成工序G,在存在HgCl2(1.53g,5.64mmol)的情况下,使5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-胺(1.11g,4.33mmol)和N,N'-双-Boc-S-甲基异硫脲(1.64g,5.65mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至石油醚:EtOAc=3:7)纯化。黄色固体(1.83g,85%)。1H NMR(CDCl3)δ1.50(s,9H),1.51(s,9H),2.81(s,3H),3.24(t,4H,J 4.0),3.37(t,4H,J 4.0),7.27(dd,1H,J 9.0&2.5),7.96(s,1H),8.24(br d,1H,J 6.5),10.7(br s,1H),11.50(br s,1H)。
4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)吗啉。使用一般合成工序G,在存在HgCl2(7.58g,27.9mmol)的情况下,使5-吗啉代吡啶-2-胺(3.85g,21.5mmol)和N,N’-双-Boc-S-甲基异硫脲(8.11g,27.9mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至石油醚:EtOAc=7:3)纯化。淡黄色固体(5.53g,61%)。1H NMR(CDCl3)δ1.45(s,9H),1.47(s,9H),3.06(t,4H,J 4.5),3.79(t,4H,J 4.5),7.20(dd,1H,J 9.0&3.0),7.90(d,1H,J 2.5),8.18(br d,1H,J 8.0),10.66(br s,1H),11.48(br s,1H)。
1-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)哌啶。使用一般合成工序G,在存在HgCl2(9.50g,35.0mmol)的情况下,使5-(哌啶-1-基)吡啶-2-胺(3.10g,17.5mmol)和N,N’-双-Boc-S-甲基异硫脲(7.60g,26.2mmol)反应,并且残余物通过快速柱色谱法(硅胶,石油醚渐变至石油醚:EtOAc=8:2)纯化。黄色固体(4.00g,54%)。1H NMR(CDCl3)δ1.50(s,9H),1.52(s,9H),1.56-1.58(m,2H),1.70(t,4H,J 5.5),3.11(t,4H,J 5.5),7.26(dd,1H,J9.0&3.0),7.96(d,1H,J 3.0),8.17(d,1H,J8.0),10.68(br s,1H),11.51(br s,1H)。
1-乙酰基-4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)-1,4-二氮杂环庚烷。使用一般合成工序G,在存在HgCl2(7.14g,26.3mmol)的情况下,使1-(4-(6-氨基吡啶-3-基)-1,4-二氮杂环庚烷-1-基)乙-1-酮(3.08g,13.1mmol)和N,N'-双-Boc-S-甲基异硫脲(5.72g,19.7mmol)反应。黄色泡沫(4.51g,72%)。1H NMR(CDCl3)(化合物作为以大约4.5:5.5比率的两种旋转异构体存在。主要旋转异构体指定为#且次要旋转异构体指定为*。)δ1.50(s),1.51(s),1.52(s)(总共18H),1.96-2.02(m,2H),2.03*(s,1.35H),2.10#(s,1.65H),3.34#(t,1.1H,J 6.0),3.42*(t,0.9H,J 6.0),3.51-3.63#,#,*,*,*(m,4.9H),3.74#(t,1.1H,J 5.0),7.06#(d,0.55H,J 9.5),7.07*(dd,0.45H,J 9.5&1.0),7.80(s,1H),8.16#(d,0.55H,J 9.0),8.19*(d,0.45H,J 9.5),10.64#(br s,0.55H),10.66*(br s,0.45H),11.51(br s,1H)。
2,2,2-三氟乙酸1-(吡啶-2-基)胍。使用一般合成工序H,使2-(2,3-双(叔丁氧基羰基)胍基)吡啶(3.60g,10.7mmol)脱保护。白色固体(2.65g,99%)。1H NMR(CD3OD)δ7.04(dt,1H,J 7.5&0.5),7.18(ddd,1H,J 7.5&5.0&1.0),7.85(ddd,1H,J 9.5&7.5&2.0),8.34(ddd,1H,J5.0&2.0&1.0)。
2,2,2-三氟乙酸1-(吡嗪-2-基)胍。使用一般合成工序H,使2-(2,3-双(叔丁氧基羰基)胍基)吡嗪(1.18g,3.50mmol)脱保护,得到为淡黄色固体的2,2,2-三氟乙酸1-(吡嗪-2-基)胍和其叔丁基化副产物以大约1:4.2的比率的混合物(1.19g,26%),其不经进一步纯化而用于下一步骤。1H NMR(CD3OD)δ8.35(s,1H),8.38(d,1H,J 1.5),8.43(s,1H)。
2,2,2-三氟乙酸1-(5-氟吡啶-2-基)胍。使用一般合成工序H,使2-(2,3-双(叔丁氧基羰基)胍基)-5-氟吡啶(4.34g,12.2mmol)脱保护。黄色固体(3.28g,100%)。1H NMR(CD3OD)δ7.11(dd,1H,J 9.0&3.5),7.72(td,1H,J 9.0&3.0),8.25(d,1H,J 3.0)。
2,2,2-三氟乙酸1-(5-氯吡啶-2-基)胍。使用一般合成工序H,使2-(2,3-双(叔丁氧基羰基)胍基)-5-氯吡啶(3.15g,8.49mmol)脱保护。白色固体(2.42g,100%)。1H NMR(CD3OD)δ7.07(d,1H,J 9.0),7.89(d,1H,J 8.5),8.34(s,1H)。
2,2,2-三氟乙酸1-(5-溴吡啶-2-基)胍。使用一般合成工序H,使2-(2,3-双(叔丁氧基羰基)胍基)-5-溴吡啶(3.70g,8.91mmol)脱保护。白色固体(2.93g,99%)。1H NMR(CD3OD)δ7.02(d,1H,J 8.5),8.01(d,1H,J 9.0),8.43(s,1H)。
2,2,2-三氟乙酸1-(5-碘吡啶-2-基)胍。使用一般合成工序H,使2-(2,3-双(叔丁氧基羰基)胍基)-5-碘吡啶(3.24g,7.01mmol)脱保护。白色固体(2.64g,100%)。1H NMR(CD3OD)δ6.91(d,1H,J 8.5),8.14(d,1H,J 8.5),8.56(s,1H)。
2,2,2-三氟乙酸1-(5-甲基吡啶-2-基)胍。使用一般合成工序H,使2-(2,3-双(叔丁氧基羰基)胍基)-5-甲基吡啶(2.81g,8.02mmol)脱保护。灰色固体(2.12g,100%)。1HNMR(CD3OD)δ2.32(s,3H),6.94(d,1H,J 8.0),7.69(d,1H,J 8.5),8.17(s,1H)。
二(2,2,2-三氟乙酸)1-(5-(哌嗪-1-基)吡啶-2-基)胍。使用一般合成工序H,使4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)哌嗪-1-羧酸叔丁酯(781mg,1.50mmol)脱保护。黄色固体(672mg,100%)。1H NMR(CD3OD)δ3.38-3.45(m,8H),7.02(d,1H,J 9.0),7.60(dd,1H,J 9.0&3.0),8.06(d,1H,J 3.0)。
1-(5-(4-甲基哌嗪-1-基)吡啶-2-基)胍。使用一般合成工序H,使1-甲基-4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)哌嗪(1.55g,3.57mmol)脱保护。将残余物溶解在CH3OH(50mL)中,并且添加过量树脂(氢氧化物形式,用H2O预溶胀30分钟且用CH3OH预溶胀30分钟)在CH3OH(50mL)中的悬浮液。将所得悬浮液在室温下搅拌过夜且过滤,并且将固体用CH3OH(50mL)洗涤。将有机洗涤液与滤液合并且在减压下浓缩,得到为黄色固体的1-(5-(4-甲基哌嗪-1-基)吡啶-2-基)胍(836mg,100%)。1H NMR(CD3OD)δ2.34(s,3H),2.61(t,4H,J 5.0),3.11(t,4H,J 5.0),6.74(d,1H,J 9.0),7.32(dd,1H,J9.0&3.0),7.85(d,1H,J 3.0)。
2,2,2-三氟乙酸1-(5-(4-乙基哌嗪-1-基)吡啶-2-基)胍。使用一般合成工序H,使1-乙基-4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)哌嗪(6.27g,14.0mmol)脱保护。黄色泡沫(6.66g,100%)。1H NMR(CD3OD)δ1.31(t,3H,J 7.5),3.14(t,2H,J 12.5),3.21(q,2H,J 7.5),3.23(t,2H,J12.5),3.69(d,2H,J 11.5),3.85(d,2H,J 12.5),7.02(d,1H,J9.0),7.60(d,1H,J 9.0&2.5),8.06(d,1H,J 2.0)。
2,2,2-三氟乙酸1-(5-(4-乙酰基哌嗪-1-基)吡啶-2-基)胍。使用一般合成工序H,使1-乙酰基-4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)哌嗪(693mg,1.50mmol)脱保护。黄色固体(564mg,100%)。1H NMR(CD3OD)δ2.15(s,3H),3.18(t,2H,J 5.0),3.24(t,2H,J5.0),3.71(t,2H,J 5.0),3.75(t,2H,J 5.0),6.96(d,1H,J 9.0),7.57(dd,1H,J 9.0&3.0),8.03(d,1H,J 2.5)。
2,2,2-三氟乙酸1-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-基)胍。使用一般合成工序H,使1-(甲基磺酰基)-4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)哌嗪(618mg,1.24mmol)脱保护。黄色固体(511mg,100%)。1H NMR(CD3OD)δ2.90(s,3H),3.30(t,4H,J4.5),3.39(t,4H,J 4.5),6.97(d,1H,J 9.0),7.58(dd,1H,J 9.0&2.0),8.04(d,1H,J2.0)。
1-(5-吗啉代吡啶-2-基)胍。使用一般合成工序H,使4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)吗啉(1.43g,3.39mmol)脱保护。将残余物溶解在CH3OH(50mL)中,并且添加过量树脂(氢氧化物形式,用H2O预溶胀30分钟且用CH3OH预溶胀30分钟)在CH3OH(25mL)中的悬浮液。将所得悬浮液在室温下搅拌过夜且过滤,并且将固体用CH3OH(100mL)洗涤。将有机洗涤液与滤液合并且在减压下浓缩,得到为淡黄色固体的1-(5-吗啉代吡啶-2-基)胍(751mg,100%)。1H NMR(CD3OD)δ3.16(t,4H,J 5.0),3.84(t,4H,J5.0),6.96(d,1H,J 9.0),7.52(dd,1H,J 9.0&3.0),7.99(d,1H,J 2.5)。
2,2,2-三氟乙酸1-(5-(哌啶-1-基)吡啶-2-基)胍。使用一般合成工序H,使1-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)哌啶(4.00g,9.54mmol)脱保护。白色固体(3.18g,100%)。1H NMR(CD3OD)δ1.69-1.78(m,2H),1.90-2.20(m,4H),3.52(t,4H,J 5.5),7.18(d,1H,J 9.5),8.00(dd,1H,J 9.5&2.5),8.46(d,1H,J 2.5)。
2,2,2-三氟乙酸1-(5-(4-乙酰基-1,4-二氮杂环庚烷-1-基)吡啶-2-基)胍。使用一般合成工序H,使1-乙酰基-4-(6-(2,3-双(叔丁氧基羰基)胍基)吡啶-3-基)-1,4-二氮杂环庚烷(572mg,1.20mmol)脱保护。黄色胶(468mg,100%)。1H NMR(DMSO-d6)δ1.71-1.79(m,1H),1.79-1.89(m,1H),1.83(s,1.5H),1.95(s,1.5H),3.30(t,1H,J 6.0),3.36(t,1H,J6.0),3.40-3.63(m,5H),3.67(t,1H,J 5.5),6.90(d,0.5H,J 9.0),6.92(d,0.5H,J 9.0),7.34(dd,0.5H,J 9.0&3.0),7.37(dd,0.5H,J 9.0&3.0),7.79(d,0.5H,J 3.0),7.81(d,0.5H,J 3.0),8.15(br s,4H),10.72(s,0.5H),10.74(s,0.5H)。
实施例
4-(咪唑并[1,2-a]吡啶-3-基)-N-(5-(哌嗪-1-基)吡啶-2-基)嘧啶-2-胺(1)。使用一般合成工序I,通过二(2,2,2-三氟乙酸)1-(5-(哌嗪-1-基)吡啶-2-基)胍(495mg,1.10mmol)与(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(216mg,1.00mmol)的反应制备。黄色固体(120mg,32%)。1H NMR(DMSO-d6)δ2.89(t,4H,J 5.0),3.07(t,4H,J5.0),7.11(td,1H,J 7.0&1.0),7.41(d,1H,J 5.5),7.43(dd,1H,J 9.0&3.0),7.50(ddd,1H,J 9.0&7.0&1.0),7.75(d,1H,J 8.5),8.00(d,1H,J9.0),8.03(d,1H,J 3.0),8.43(d,1H,J 5.5),8.62(s,1H),9.99(s,1H),10.38(d,1H,J 7.0)。HRMS m/z 373.1886[M+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)嘧啶-2-胺 (2)。使用一般合成工序I,通过1-(5-(4-甲基哌嗪-1-基)吡啶-2-基)胍(282mg,1.20mmol)与(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(216mg,1.00mmol)的反应制备。黄色固体(170mg,44%)。1H NMR(DMSO-d6)δ2.22(s,3H),2.47(t,4H,J 5.0),3.13(t,4H,J 5.0),7.11(td,1H,J 6.5&1.0),7.41(d,1H,J 5.0),7.44(dd,1H,J9.5&3.0),7.50(ddd,1H,J 9.0&7.0&1.5),7.75(d,1H,J 9.0),8.00(d,1H,J 9.0),8.04(d,1H,J 3.0),8.43(d,1H,J 5.0),8.61(s,1H),10.00(s,1H),10.38(d,1H,J 7.0)。HRMS m/z 387.2047[M+H]+。
1-(4-(6-((4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1- 基)乙-1-酮(3)。使用一般合成工序I,通过2,2,2-三氟乙酸1-(5-(4-乙酰基哌嗪-1-基)吡啶-2-基)胍(564mg,1.50mmol)与(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(216mg,1.00mmol)的反应制备。黄色固体(240mg,58%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.08(t,2H,J 5.0),3.15(t,2H,J 5.0),3.60(t,2H,J 5.5),3.61(t,2H,J5.5),7.12(td,1H,J 7.0&1.0),7.42(d,1H,J 5.5),7.48(dd,1H,J 9.0&3.0),7.50(ddd,1H,J9.0&7.0&1.0),7.75(d,1H,J 9.0),8.03(d,1H,J9.0),8.08(d,1H,J 3.0),8.44(d,1H,J5.5),8.62(s,1H),10.04(s,1H),10.39(d,1H,J 7.0)。HRMS m/z 415.1989[M+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-N-(5-吗啉代吡啶-2-基)嘧啶-2-胺(4)。使用一般合成工序I,通过1-(5-吗啉代吡啶-2-基)胍(221mg,957μmol)与(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(172mg,799μmol)的反应制备。稻草样固体(140mg,47%)。1H NMR(DMSO-d6)δ3.10(t,4H,J 5.0),3.75(t,4H,J 5.0),7.12(td,1H,J7.0&1.0),7.39(d,1H,J 5.5),7.44(dd,1H,J 9.5&3.0),7.51(ddd,1H,J 9.0&6.5&1.0),7.74(d,1H,J 9.0),7.97(d,1H,J 9.0),8.04(d,1H,J 3.0),8.42(d,1H,J 5.5),8.58(s,1H),9.91(s,1H),10.32(d,1H,J 7.0)。HRMS m/z 374.1728[M+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-N-(5-(哌啶-1-基)吡啶-2-基)嘧啶-2-胺(5)。使用一般合成工序I,通过2,2,2-三氟乙酸1-(5-(哌啶-1-基)吡啶-2-基)胍(320mg,960μmol)与(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(172mg,799μmol)的反应制备。黄色固体(50mg,17%)。1H NMR(DMSO-d6)δ1.48-1.54(m,2H),1.59-1.65(m,4H),3.09(t,4H,J 5.5),7.11(td,1H,J 7.0&1.0),7.37(d,1H,J 5.5),7.42(dd,1H,J 9.0&3.0),7.51(ddd,1H,J 8.0&6.5&1.0),7.72(d,1H,J 9.0),7.88(d,1H,J 9.0),8.01(d,1H,J3.0),8.40(d,1H,J 5.5),8.54(s,1H),9.78(s,1H),10.26(d,1H,J 7.0)。HRMS m/z372.1934[M+H]+。
1-(4-(6-((4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)-1,4-二 氮杂环庚烷-1-基)乙-1-酮(6)。使用一般合成工序I,通过2,2,2-三氟乙酸1-(5-(4-乙酰基-1,4-二氮杂环庚烷-1-基)吡啶-2-基)胍(468mg,1.20mmol)与(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(216mg,1.00mmol)的反应制备。黄色固体(195mg,45%)。1H NMR(DMSO-d6)δ1.78-1.83(m,1H),1.84(s,1.5H),1.85-1.90(m,1H),1.97(s,1.5H),3.34(t,1H,J 6.0),3.38(t,1H,J 6.0),3.46-3.74(m,6H),7.10(td,1H,J 7.0&1.0),7.22-7.28(m,1H),7.35(d,1H,J 5.5),7.49(ddd,1H,J 8.0&7.0&1.0),7.73(d,1H,J9.0),7.85(d,0.5H,J 10.0),7.87(d,0.5H,J 10.5),7.89(d,0.5H,J 4.5),7.90(d,0.5H,J3.5),8.39(d,1H,J 5.5),8.56(s,0.5H),8.57(s,0.5H),9.73(s,0.5H),9.74(s,0.5H),10.29(d,1H,J 6.5)。HRMS m/z 429.2148[M+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-N-(吡啶-2-基)嘧啶-2-胺(7)。使用一般合成工序I,通过2,2,2-三氟乙酸1-(吡啶-2-基)胍(240mg,959μmol)与(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(172mg,799μmol)的反应制备。米黄色固体(115mg,50%)。1H NMR(DMSO-d6)δ7.02(ddd,1H,J 7.5&5.0&1.0),7.14(dt,1H,J 7.0&1.5),7.45(d,1H,J 5.5),7.52(ddd,1H,J 9.0&7.0&1.5),7.73(td,1H,J 9.0&1.0),7.76(ddd,1H,J 9.0&7.5&2.0),8.08(d,1H,J 8.5),8.32(ddd,1H,J 5.0&2.0&0.5),8.46(d,1H,J 5.5),8.56(s,1H),10.06(s,1H),10.32(td,1H,J 7.0&1.0)。HRMS m/z 289.1201[M+H]+。
1-(4-(6-((4-(6-氟咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌 嗪-1-基)乙-1-酮(8)。使用一般合成工序I,通过2,2,2-三氟乙酸1-(5-(4-乙酰基哌嗪-1-基)吡啶-2-基)胍(452mg,1.20mmol)与(E)-3-(二甲基氨基)-1-(6-氟咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(234mg,1.00mmol)的反应制备。米黄色固体(220mg,51%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.08(t,2H,J 5.0),3.15(t,2H,J 5.0),3.60(t,2H,J 4.0),3.61(t,2H,J 4.0),7.43(d,1H,J 5.5),7.48(dd,1H,J 9.0&3.0),7.58(ddd,1H,J 10.0&8.0&2.5),7.82(dd,1H,J 10.0&5.5),7.91(br d,1H,J 6.5),8.09(d,1H,J 3.0),8.46(d,1H,J5.0),8.67(s,1H),10.25(br s,1H),10.59(dd,1H,J 5.5&2.0)。HRMS m/z 433.1895[M+H]+。
1-(4-(6-((4-(6-氯咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌 嗪-1-基)乙-1-酮(9)。使用一般合成工序I,通过2,2,2-三氟乙酸1-(5-(4-乙酰基哌嗪-1-基)吡啶-2-基)胍(452mg,1.20mmol)与(E)-3-(二甲基氨基)-1-(6-氯咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(250mg,1.00mmol)的反应制备。黄色固体(291mg,65%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.08(t,2H,J 5.0),3.15(t,2H,J 5.0),3.59(t,2H,J 4.0),3.60(t,2H,J4.0),7.43(d,1H,J 5.5),7.48(dd,1H,J 9.0&3.0),7.53(dd,1H,J 9.5&2.0),7.79(dd,1H,J 9.5&0.5),7.88(br d,1H,J 8.0),8.12(d,1H,J 3.0),8.46(d,1H,J 5.5),8.66(s,1H),10.20(br s,1H),10.34(d,1H,J 2.0)。HRMS m/z 449.1604[M(35Cl)+H]+,451.1571[M(37Cl)+H]+。
1-(4-(6-((4-(6-溴咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌 嗪-1-基)乙-1-酮(10)。使用一般合成工序I,通过2,2,2-三氟乙酸1-(5-(4-乙酰基哌嗪-1-基)吡啶-2-基)胍(452mg,1.20mmol)与(E)-3-(二甲基氨基)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(295mg,1.00mmol)的反应制备。黄色固体(351mg,71%)。1H NMR(DMSO-d6)δ2.04(s,3H),3.07(t,2H,J 5.0),3.13(t,2H,J 5.0),3.55-3.60(m,4H),7.39(d,1H,J5.5),7.47(dd,1H,J 9.0&3.0),7.60(dd,1H,J 9.5&2.0),7.70(d,1H,J 9.5),7.76(br d,1H,J 8.0),8.11(d,1H,J 3.0),8.42(d,1H,J 5.5),8.55(s,1H),9.92(s,1H),10.21(s,1H)。HRMS m/z 493.1091[M(79Br)+H]+,495.1075[M(81Br)+H]+。
1-(4-(6-((4-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 3-基)哌嗪-1-基)乙-1-酮(11)。使用一般合成工序I,通过2,2,2-三氟乙酸1-(5-(4-乙酰基哌嗪-1-基)吡啶-2-基)胍(452mg,1.20mmol)与(E)-3-(二甲基氨基)-1-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(284mg,1.00mmol)的反应制备。黄色固体(306mg,63%)。1HNMR(DMSO-d6)δ2.05(s,3H),3.08(t,2H,J 5.0),3.14(t,2H,J 5.0),3.55-3.65(m,4H),7.42(dd,1H,J 9.0&3.0),7.47(d,1H,J 5.5),7.70(dd,1H,J 9.5&2.0),7.89(d,1H,J9.0),7.96(br d,1H,J 9.5),8.07(d,1H,J 3.0),8.51(d,1H,J 5.0),8.75(s,1H),10.06(s,1H),10.34(s,1H)。HRMS m/z 483.1865[M+H]+。
1-(4-(6-((4-(6-(呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 3-基)哌嗪-1-基)乙-1-酮(12)。使用一般合成工序J,通过10(247mg,501μmol)与呋喃-2-基硼酸(67.3mg,601μmol)的反应制备。黄色固体(195mg,81%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.03(t,2H,J 5.0),3.09(t,2H,J 5.0),3.57(t,2H,J 4.0),3.58(t,2H,J 4.0),6.65(dd,1H,J 3.0&1.5),7.05(d,1H,J 3.0),7.32(dd,1H,J 9.0&3.0),7.42(d,1H,J 5.5),7.71(d,1H,J 1.5),7.82(s,1H),7.94(d,1H,J 9.0),8.03(d,1H,J 3.0),8.47(d,1H,J5.5),8.58(s,1H),9.87(s,1H),10.15(s,1H)。HRMS m/z 481.2099[M+H]+。
1-(4-(6-((4-(6-甲基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌 嗪-1-基)乙-1-酮(13)。使用一般合成工序I,通过2,2,2-三氟乙酸1-(5-(4-乙酰基哌嗪-1-基)吡啶-2-基)胍(452mg,1.20mmol)与(E)-3-(二甲基氨基)-1-(6-甲基咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(230mg,1.00mmol)的反应制备。黄色固体(149mg,35%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.42(s,3H),3.08(t,2H,J 5.0),3.15(t,2H,J5.0),3.59(t,2H,J5.5),3.60(t,2H,J 5.5),7.35(dd,1H,J 9.0&1.0),7.40(d,1H,J 5.5),7.48(dd,1H,J9.5&3.0),7.66(d,1H,J 9.0),8.07(d,1H,J 9.0),8.08(d,1H,J 3.0),8.41(d,1H,J 5.5),8.56(s,1H),9.99(s,1H),10.07(s,1H)。HRMS m/z 429.2147[M+H]+。
1-(4-(6-((4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌 嗪-1-基)乙-1-酮(14)。使用一般合成工序J,通过10(247mg,501μmol)与苯基硼酸(73.2mg,600μmol)的反应制备。黄色固体(198mg,80%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.90(t,2H,J5.0),2.97(t,2H,J 4.5),3.55(t,2H,J 5.0),3.56(t,2H,J 5.0),7.14(d,1H,J 7.0),7.42(d,1H,J 5.5),7.43(t,1H,J 6.5),7.48(t,2H,J 6.0),7.68(d,2H,J 6.0),7.76(dd,1H,J9.0&1.5),7.80-7.88(m,3H),8.47(d,1H,J 5.0),8.59(s,1H),9.96(s,1H),10.19(s,1H)。HRMS m/z 491.2308[M+H]+。
1-(4-(6-((4-(6-(吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 3-基)哌嗪-1-基)乙-1-酮(15)。使用一般合成工序J,通过10(247mg,501μmol)与吡啶-3-基硼酸(73.8mg,600μmol)的反应制备。黄色固体(198mg,80%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.95(t,2H,J 5.0),3.02(t,2H,J 4.5),3.56(t,2H,J 5.0),3.58(t,2H,J 5.0),7.23(d,1H,J 8.0),7.44(d,1H,J 5.5),7.52(dd,1H,J 8.0&5.5),7.81(dd,1H,J9.0&2.0),7.88(d,1H,J 9.0),7.89(d,1H,J 5.5),7.93(d,1H,J 8.5),8.10(d,1H,J 8.0),8.47(d,1H,J5.5),8.63(s,1H),8.64(dd,1H,J 5.0&1.0),8.96(dd,1H,J 2.0),10.10(s,1H),10.30(d,1H,J 7.0)。HRMS m/z492.2257[M+H]+。
1-(4-(6-((4-(6-(嘧啶-5-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 3-基)哌嗪-1-基)乙-1-酮(16)。使用一般合成工序J,通过10(247mg,501μmol)与5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(124mg,602μmol)的反应制备。黄色固体(200mg,81%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.99(t,2H,J 5.0),3.06(t,2H,J 5.0),3.58(t,2H,J 4.5),3.59(t,2H,J 4.5),7.31(d,1H,J 7.5),7.45(d,1H,J 5.0),7.87(dd,1H,J9.5&1.5),7.92(d,1H,J 9.5),7.94(s,1H),8.02(d,1H,J 7.5),8.48(d,1H,J 5.5),8.67(s,1H),9.20(s,2H),9.26(s,1H),10.20(br s,1H),10.40(s,1H)。HRMS m/z 493.2208[M+H]+。
1-(4-(6-((4-(6-(噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 3-基)哌嗪-1-基)乙-1-酮(17)。使用一般合成工序J,通过10(197mg,399μmol)与噻吩-2-基硼酸(61.3mg,479μmol)的反应制备。淡黄色固体(146mg,74%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.97(t,2H,J 5.0),3.04(t,2H,J 5.0),3.56(t,2H,J 5.0),3.57(t,2H,J 5.0),7.17(dd,1H,J 5.0&3.5),7.25(dd,1H,J 9.0&3.0),7.42(d,1H,J 5.0),7.51(d,1H,J 3.0),7.61(dd,1H,J 5.0&1.0),7.72(dd,1H,J 9.0&1.5),7.81(dd,1H,J 9.0&0.5),7.88(d,1H,J9.0),7.95(d,1H,J 2.5),8.48(d,1H,J5.0),8.58(s,1H),9.88(s,1H),10.18(d,1H,J0.5)。HRMS m/z 497.1874[M+H]+。
1-(4-(6-((4-(6-(2-氨基嘧啶-5-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨 基)吡啶-3-基)哌嗪-1-基)乙-1-酮(18)。使用一般合成工序J,通过10(197mg,399μmol)与(2-氨基嘧啶-5-基)硼酸(66.6mg,479μmol)的反应制备。稻草样固体(76mg,37%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.99(t,2H,J 5.0),3.05(t,2H,J 5.0),3.58(t,2H,J 5.0),3.59(t,2H,J 5.0),6.88(s,2H),7.29(dd,1H,J 7.5&2.0),7.42(d,1H,J 5.5),7.72(dd,1H,J9.0&1.5),7.82(dd,1H,J 9.5&0.5),7.92(d,1H,J 2.5),7.96(d,1H,J 9.0),8.46(d,1H,J5.5),8.59(s,1H),8.60(s,2H),10.12(br s,1H),10.19(s,1H)。HRMS m/z 508.2317[M+H]+。
1-(4-(6-((4-(6-(2-甲氧基嘧啶-5-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨 基)吡啶-3-基)哌嗪-1-基)乙-1-酮(19)。使用一般合成工序J,通过10(197mg,399μmol)与(2-甲氧基嘧啶-5-基)硼酸(73.8mg,479μmol)的反应制备。黄色固体(190mg,91%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.97(t,2H,J 4.5),3.05(t,2H,J 4.5),3.57(t,2H,J 5.0),3.58(t,2H,J 5.0),4.00(s,3H),7.31(d,1H,J 8.0),7.44(d,1H,J 5.0),7.81(dd,1H,J 9.0&1.5),7.88(d,1H,J 9.0),7.94(d,1H,J 2.5),8.01(br d,1H,J 8.5),8.47(d,1H,J 5.5),8.65(s,1H),8.97(s,2H),10.17(br s,1H),10.32(s,1H)。HRMS m/z 523.2311[M+H]+。
1-(4-(6-((4-(6-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)咪唑并[1,2-a]吡啶-3-基) 嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮(20)。使用一般合成工序J,通过10(197mg,399μmol)与2-(4-甲基哌嗪-1-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(146mg,480μmol)的反应制备。米黄色固体(198mg,84%)。1H NMR(DMSO-d6)δ2.04(s,3H),2.21(s,3H),2.36(t,4H,J 5.0),2.97(t,2H,J 4.5),3.04(t,2H,J 4.5),3.56(t,2H,J 5.5),3.57(t,2H,J 5.5),3.79(t,4H,J 5.0),7.32(d,1H,J 7.5),7.39(d,1H,J5.5),7.72(dd,1H,J 9.0&1.5),7.81(d,1H,J 9.5),7.94(d,1H,J 1.5),7.99(d,1H,J7.5),8.44(d,1H,J 5.5),8.58(s,1H),8.71(s,2H),10.14(br s,1H),10.20(s,1H)。HRMSm/z 591.3052[M+H]+。
1-(4-(6-((4-(6-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基) 吡啶-3-基)哌嗪-1-基)乙-1-酮(21)。使用一般合成工序J,通过10(197mg,399μmol)与2-(苯并呋喃-2-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(117mg,479μmol)的反应制备。黄色固体(166mg,78%)。1H NMR(DMSO-d6)δ1.99(s,3H),2.72(t,2H,J 5.0),2.76(t,2H,J5.0),3.34-3.38(m,4H),7.17(dd,1H,J 9.0&2.5),7.27(td,1H,J 8.0&1.5),7.32(td,1H,J8.0&1.5),7.38(d,1H,J 8.5),7.44(d,1H,J 5.5),7.49(s,1H),7.68(d,1H,J 7.5),7.89(dd,1H,J 9.0&1.0),7.20(d,1H,J 9.0),7.97(dd,1H,J 6.5&1.5),7.98(s,1H),8.51(d,1H,J 5.5),8.61(s,1H),9.94(s,1H),10.37(s,1H)。HRMS m/z 531.2259[M+H]+。
1-(4-(6-((4-(6-(苯并[b]噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨 基)吡啶-3-基)哌嗪-1-基)乙-1-酮(222)。使用一般合成工序J,通过10(197mg,399μmol)与苯并[b]噻吩-2-基硼酸(85.4mg,480μmol)的反应制备。黄色固体(160mg,73%)。1H NMR(DMSO-d6)δ1.99(s,3H),2.66(t,2H,J 5.0),2.70(t,2H,J 5.0),3.34-3.38(m,4H),7.14(dd,1H,J 9.0&3.0),7.35-7.44(m,2H),7.44(d,1H,J 5.0),7.79(s,1H),7.80(d,1H,J8.5),7.83(dd,1H,J 9.0&1.5),7.84(d,1H,J 8.0),7.88(dd,1H,J 10.0&0.5),7.89(d,1H,J 3.0),7.96(d,1H,J 8.0),8.50(d,1H,J 5.0),8.61(s,1H),9.89(s,1H),10.30(s,1H)。HRMS m/z 547.2026[M+H]+。
1-(4-(6-((4-(6-(1H-吡咯-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡 啶-3-基)哌嗪-1-基)乙-1-酮(23)。使用一般合成工序J,通过10(197mg,399μmol)与3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-(三异丙基甲硅烷基)-1H-吡咯(168mg,481μmol)在130℃下反应1小时,然后在160℃下反应1小时制备。黄色固体(150mg,79%)。1HNMR(DMSO-d6)δ2.04(s,3H),2.99(t,2H,J 5.0),3.05(t,2H,J 5.0),3.57(t,2H,J 4.5),3.58(t,2H,J 4.5),6.41(br s,1H),6.82(dd,1H,J 4.5&2.5),7.28(dd,1H,J 9.0&3.0),7.31(br s,1H),7.38(d,1H,J 5.5),7.69(d,1H,J 9.0),7.30(dd,1H,J 9.0&1.5),7.93(d,1H,J 9.0),8.00(d,1H,J 3.0),8.43(d,1H,J 5.5),8.48(s,1H),9.85(s,1H),9.94(s,1H),11.03(br s,1H)。HRMS m/z 480.2264[M+H]+。
1-(4-(6-((4-(6-(1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡 啶-3-基)哌嗪-1-基)乙-1-酮(24)。使用一般合成工序J,通过10(197mg,399μmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-羧酸叔丁酯(141mg,479μmol)的反应制备。米黄色固体(100mg,52%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.02(t,2H,J 5.0),3.08(t,2H,J 5.0),3.58(t,2H,J 6.0),3.61(t,2H,J 6.5),7.33(dd,1H,J9.0&3.0),7.41(d,1H,J 5.5),7.77(s,1H),7.78(s,1H),8.00(d,1H,J9.5),8.01(d,1H,J 2.5),8.19(brs,2H),8.44(d,1H,J 5.5),8.56(s,1H),10.06(s,1H),10.10(s,1H),13.08(br s,1H)。HRMSm/z 481.2212[M+H]+。
1-(4-(6-((4-(6-(呋喃-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 3-基)哌嗪-1-基)乙-1-酮(25)。使用一般合成工序J,通过10(148mg,300μmol)与2-(呋喃-3-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(69.9mg,360μmol)的反应制备。淡棕色固体(75mg,52%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.02(t,2H,J 5.0),3.09(t,2H,J 5.0),3.58(t,2H,J 5.0),3.59(t,2H,J 5.0),6.99(s,1H),7.35(dd,1H,J 9.0&3.0),7.42(d,1H,J 5.5),7.75(dd,1H,J 9.0&1.5),7.79(d,1H,J 8.5),7.80(t,1H,J 1.5),7.96(d,1H,J9.0),8.02(d,1H,J 3.0),8.29(s,1H),8.45(d,1H,J 5.0),8.57(s,1H),10.00(s,1H),10.06(s,1H)。HRMS m/z481.2099[M+H]+。
1-(4-(6-((4-(6-(噻吩-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 3-基)哌嗪-1-基)乙-1-酮(26)。使用一般合成工序J,通过10(148mg,300μmol)与4,4,5,5-四甲基-2-(噻吩-3-基)-1,3,2-二氧杂环戊硼烷(75.7mg,360μmol)的反应制备。黄色固体(115mg,77%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.00(t,2H,J 4.5),3.06(t,2H,J 4.0),3.50-3.65(m,4H),7.28(dd,1H,J 8.5&2.0),7.41(d,1H,J 5.0),7.52(d,1H,J 4.0),7.67(dd,1H,J 5.0&3.0),7.80(d,1H,J 9.5),7.85(d,1H,J10.0),7.92(d,1H,J 9.0),7.95-8.02(m,2H),8.46(d,1H,J 5.0),8.57(s,1H),9.97(s,1H),10.17(s,1H)。HRMS m/z497.1864[M+H]+。
1-(4-(6-((4-(6-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基) 氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮(27)。使用一般合成工序J,通过10(148mg,300μmol)与1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(74.9mg,360μmol)的反应制备。黄色固体(85mg,57%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.01(t,2H,J 5.0),3.08(t,2H,J 5.0),3.58(t,2H,J 6.0),3.61(t,2H,J 4.0),3.88(s,3H),7.33(dd,1H,J9.0&2.5),7.41(d,1H,J 5.5),7.71(dd,1H,J 9.5&1.5),7.77(d,1H,J 9.5),7.91(br s,1H),7.96(d,1H,J 9.0),8.01(d,1H,J 3.0),8.17(br s,1H),8.44(d,1H,J 5.5),8.55(s,1H),10.00(s,1H),10.06(s,1H)。HRMS m/z 495.2361[M+H]+。
1-(4-(6-((4-(6-(苯基氨基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶- 3-基)哌嗪-1-基)乙-1-酮(28)。使用一般合成工序K,通过10(395mg,801μmol)与苯胺(87.6μL,961μmol)的反应制备。淡黄色固体(128mg,32%)。1H NMR(DMSO-d6)δ2.04(s,3H),2.91(t,2H,J 5.0),2.97(t,2H,J 5.0),3.48-3.55(m,4H),6.82(t,1H,J 7.0),7.00(d,2H,J8.0),7.24(t,2H,J 8.0),7.29(dd,1H,J 9.0&3.0),7.39(d,1H,J 5.5),7.42(dd,1H,J9.5&2.0),7.70(d,1H,J 9.5),7.90(d,1H,J 9.0),8.01(d,1H,J 3.0),8.03(s,1H),8.44(d,1H,J 5.5),8.51(s,1H),9.41(s,1H),10.06(d,1H,J2.0)。HRMS m/z 506.2418[M+H]+。
1-(4-(6-((5-氟-4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌 嗪-1-基)乙-1-酮(29)。使用一般合成工序K,通过3-(2-氯-5-氟嘧啶-4-基)咪唑并[1,2-a]吡啶(249mg,1.00mmol)与1-(4-(6-氨基吡啶-3-基)哌嗪-1-基)乙-1-酮(232mg,1.05mmol)的反应制备。淡黄色固体(155mg,36%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.09(t,2H,J 5.0),3.15(t,2H,J 5.0),3.60(t,2H,J 5.0),3.61(t,2H,J 5.0),7.18(td,1H,J7.0&1.0),7.48(dd,1H,J 9.0&3.0),7.59(dd,1H,J 7.0&1.0),7.82(d,1H,J 9.0),7.90(d,1H,J 9.0),8.08(d,1H,J 3.0),8.43(d,1H,J 4.0),8.56(d,1H,J 3.5),10.15(s,1H),10.46(d,1H,J7.0)。HRMS m/z433.1895[M+H]+。
1-(4-(6-((5-氟-4-(6-氟咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3- 基)哌嗪-1-基)乙-1-酮(30)。使用一般合成工序K,通过3-(2-氯-5-氟嘧啶-4-基)-6-氟咪唑并[1,2-a]吡啶(267mg,1.00mmol)与1-(4-(6-氨基吡啶-3-基)哌嗪-1-基)乙-1-酮(232mg,1.05mmol)的反应制备。黄色固体(84mg,19%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.08(t,2H,J 5.0),3.15(t,2H,J 4.5),3.61(s,4H),7.48(dd,1H,J 9.0&2.5),7.67(td,1H,J9.5&2.0),7.75(d,1H,J 8.5),7.88(dd,1H,J 9.5&5.5),8.10(d,1H,J 2.5),8.46(d,1H,J4.0),8.59(d,1H,J 3.5),10.34(s,1H),10.70(d,1H,J 3.5)。HRMS m/z 451.1804[M+H]+。
1-(4-(6-((5-氟-4-(6-甲基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3- 基)哌嗪-1-基)乙-1-酮(31)。使用一般合成工序K,通过3-(2-氯-5-氟嘧啶-4-基)-6-甲基咪唑并[1,2-a]吡啶(263mg,1.00mmol)与1-(4-(6-氨基吡啶-3-基)哌嗪-1-基)乙-1-酮(232mg,1.05mmol)的反应制备。黄色固体(140mg,31%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.43(s,3H),3.08(t,2H,J 5.0),3.15(t,2H,J 4.5),3.59(t,2H,J 4.5),3.60(t,2H,J4.5),7.44(d,1H,J 9.0),7.48(dd,1H,J 9.0&2.0),7.72(d,1H,J9.0),7.96(d,1H,J 9.0),8.07(d,1H,J 2.0),8.38(d,1H,J 4.0),8.55(d,1H,J 3.5),10.00(s,1H),10.17(s,1H)。HRMS m/z 447.2054[M+H]+。
1-(4-(6-((5-氟-4-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基) 吡啶-3-基)哌嗪-1-基)乙-1-酮(32)。使用一般合成工序K,通过3-(2-氯-5-氟嘧啶-4-基)-6-(三氟甲基)咪唑并[1,2-a]吡啶(317mg,1.00mmol)与1-(4-(6-氨基吡啶-3-基)哌嗪-1-基)乙-1-酮(232mg,1.05mmol)的反应制备。黄色固体(256mg,51%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.06(t,2H,J 5.0),3.12(t,2H,J 5.0),3.52-3.64(m,4H),7.40(dd,1H,J 9.0&3.0),7.76(d,1H,J 9.0),7.77(dd,1H,J 9.5&2.0),8.00(d,1H,J 9.0),8.04(d,1H,J3.0),8.51(d,1H,J 4.0),8.64(d,1H,J 3.5),10.11(s,1H),10.30(s,1H)。HRMS m/z501.1769[M+H]+。
1-(4-(6-((4-(6-(苯并呋喃-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基) 吡啶-3-基)哌嗪-1-基)乙-1-酮(33)。使用一般合成工序J,通过10(198mg,401μmol)与2-(苯并呋喃-3-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(117mg,479μmol)的反应制备。橙色固体(185mg,87%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.77(t,2H,J 5.0),2.84(t,2H,J5.0),3.45-3.54(m,4H),7.03(dd,1H,J 9.0&2.5),7.29(t,1H,J 7.5),7.40(t,1H,J 8.0),7.44(d,1H,J 5.0),7.69(d,1H,J 8.5),7.75(d,1H,J 3.0),7.79(d,1H,J 8.5),7.80(dd,1H,J 9.0&1.5),7.81(d,1H,J 9.5),7.89(d,1H,J 9.0),8.43(s,1H),8.48(d,1H,J 5.5),8.62(s,1H),9.75(s,1H),10.34(s,1H)。HRMS m/z 531.2249[M+H]+。
1-(4-(6-((4-(6-(1-(苯基磺酰基)-1H-吲哚-3-基)咪唑并[1,2-a]吡啶-3-基)嘧 啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮(34)。使用一般合成工序K,通过10(494mg,1.00mmol)与1-(苯基磺酰基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(460mg,1.20mmol)的反应制备。棕褐色固体(441mg,66%)。1H NMR(DMSO-d6)δ2.04(s,3H),2.72(t,2H,J 5.0),2.76(t,2H,J 5.0),3.42-3.52(m,4H),6.93(dd,1H,J8.5&1.5),7.29(t,1H,J 8.0),7.42(d,1H,J 5.5),7.43(t,1H,J 8.0),7.56(t,2H,J 8.0),7.67(t,1H,J 7.5),7.69(d,1H,J 3.0),7.76(d,1H,J 8.0),7.78(dd,1H,J 9.0&1.5),7.80(d,1H,J9.0),7.85(d,1H,J 9.0),8.07(d,1H,J 8.5),8.11(d,2H,J 7.5),8.28(s,1H),8.48(d,1H,J 5.0),8.58(s,1H),9.78(s,1H),10.34(s,1H)。HRMS m/z 670.2343[M+H]+。
1-(4-(6-((4-(6-(苯并[b]噻吩-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨 基)吡啶-3-基)哌嗪-1-基)乙-1-酮(35)。使用一般合成工序K,通过10(198mg,401μmol)与苯并[b]噻吩-3-基硼酸(85.4mg,480μmol)的反应制备。淡黄色固体(185mg,84%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.70(t,2H,J 5.0),2.77(t,2H,J 5.0),3.43-3.53(m,4H),6.84(d,1H,J 8.5),7.43(t,1H,J 7.5),7.44(d,1H,J 6.0),7.46(d,1H,J 7.0),7.60(d,1H,J2.5),7.68(d,1H,J 9.0),7.69(dd,1H,J 9.5&1.5),7.88(d,2H,J 9.0),7.97(s,1H),8.12(d,1H,J 8.0),8.47(d,1H,J 5.5),8.63(s,1H),9.75(s,1H),10.30(s,1H)。HRMS m/z547.2024[M+H]+。
1-(4-(6-((4-(6-(1H-吲哚-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡 啶-3-基)哌嗪-1-基)乙-1-酮(36)。使用一般合成工序K,通过10(198mg,401μmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(117mg,481μmol)的反应制备。灰白色固体(120mg,57%)。1H NMR(DMSO-d6)δ2.06(s,3H),2.68(t,2H,J 5.0),2.71(t,2H,J5.0),3.49(t,2H,J 5.5),3.51(t,2H,J 4.5),6.58(app s,1H),6.63(d,1H,J 7.0),7.19(dd,1H,J 7.0&1.0),7.22(t,1H,J 7.5),7.41-7.44(m,1H),7.42(d,1H,J 5.5),7.51(d,1H,J 7.5),7.55(d,1H,J 2.5),7.62(d,1H,J9.0),7.76(dd,1H,J 9.5&2.0),7.85(d,1H,J9.5),8.46(d,1H,J 5.0),8.58(s,1H),9.54(s,1H),10.27(s,1H),11.38(s,1H)。HRMS m/z530.2426[M+H]+。
1-(4-(6-((4-(6-(1H-吲哚-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡 啶-3-基)哌嗪-1-基)乙-1-酮(37)。使用一般合成工序K,通过10(198mg,401μmol)与2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(117mg,481μmol)的反应制备。黄色固体(140mg,66%)。1H NMR(DMSO-d6)δ2.02(s,3H),2.80(app s,2H),2.84(app s,2H),3.43-3.53(m,4H),6.94(br s,1H),7.04(t,1H,J 7.5),7.16(t,1H,J 7.5),7.19(app brs,1H),7.43(d,1H,J 8.0),7.44(d,1H,J 5.5),7.58(d,1H,J8.0),7.85(d,1H,J 9.5),7.90-7.98(m,1H),7.96(dd,1H,J 9.5&1.5),8.00(d,1H,J 9.0),8.49(d,1H,J 5.0),8.59(s,1H),9.91(s,1H),10.32(s,1H),11.73(s,1H)。HRMS m/z 530.2431[M+H]+。
1-(4-(6-((4-(6-(1-(苯基磺酰基)-1H-吡咯并[2,3-b]吡啶-3-基)咪唑并[1,2- a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮(38)。使用一般合成工序K,通过10(494mg,1.00mmol)与1-(苯基磺酰基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡咯并[2,3-b]吡啶(461mg,1.20mmol)的反应制备。淡黄色固体(524mg,78%)。1H NMR(DMSO-d6)δ2.04(s,3H),2.66(t,2H,J 5.0),2.67(t,2H,J 5.0),3.43(t,2H,J5.5),3.45(t,2H,J 5.0),6.88(d,1H,J 8.5),7.24(dd,1H,J8.0&5.0),7.40(d,1H,J 5.5),7.60(t,2H,J 8.0),7.61(d,1H,J 8.0),7.69(d,1H,J 7.5),7.71(dd,1H,J 10.0&2.5),7.84(s,2H),8.10(d,1H,J8.0),8.18(d,2H,J 7.5),8.35(s,1H),8.40(d,1H,J 5.0),8.46(d,1H,J5.5),8.55(s,1H),9.78(s,1H),10.35(s,1H)。HRMS m/z 671.2319[M+H]+。
1-(4-(6-((4-(6-(1-甲基-1H-吲哚-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基) 氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮(39)。使用一般合成工序K,通过10(198mg,401μmol)与1-甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(124mg,482μmol)的反应制备。黄色固体(125mg,57%)。1H NMR(DMSO-d6)δ2.03(s,3H),2.55(app s,4H),3.76(s,3H),6.76(s,1H),7.05(d,1H,J 8.5),7.10(t,1H,J 7.5),7.23(t,1H,J 7.5),7.45(d,1H,J 5.5),7.52(d,2H,J 8.0),7.62(d,1H,J 8.0),7.69(d,2H,J 9.0),7.87(d,1H,J9.0),8.47(d,1H,J 5.5),8.65(s,1H),9.94(s,1H),10.45(s,1H)(四种质子信号(2×CH2)由于与DMSO残余峰重叠而没有观察到)。HRMS m/z 544.2593[M+H]+。
1-(4-(6-((4-(6-(1-甲基-1H-吲哚-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基) 氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮(40)。使用一般合成工序K,通过10(198mg,401μmol)与1-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(124mg,482μmol)的反应制备。米黄色固体(166mg,76%)。1H NMR(DMSO-d6)δ2.04(s,3H),2.68(t,2H,J 5.0),2.76(t,2H,J 5.0),3.44-3.52(m,4H),3.85(s,3H),6.88(dd,1H,J 9.0&2.5),7.10(t,1H,J7.5),7.24(t,1H,J 7.5),7.41(d,1H,J 5.5),7.53(d,1H,J 8.0),7.70-7.73(m,1H),7.72(s,1H),7.75-7.80(m,3H),7.82(d,1H,J 9.0),8.47(d,1H,J 5.5),8.54(s,1H),9.58(s,1H),10.22(s,1H)。HRMS m/z 544.2587[M+H]+。
1-(4-(6-((4-(6-(1H-吲哚-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡 啶-3-基)哌嗪-1-基)乙-1-酮(41)。根据一般合成工序L,通过使38(335mg,500μmol)脱保护制备。黄色固体(200mg,75%)。1H NMR(DMSO-d6)δ2.04(s,3H),2.72(t,2H,J 5.0),2.76(t,2H,J 5.0),3.45(t,2H,J 5.0),3.48(t,2H,J 5.0),6.84(dd,1H,J 9.0&2.5),7.08(t,1H,J7.5),7.18(t,1H,J 7.5),7.41(d,1H,J 5.0),7.49(d,1H,J 8.0),7.70(d,1H,J 3.0),7.78(d,1H,J 9.0),7.78-7.84(m,4H),8.47(d,1H,J 5.0),8.54(s,1H),8.55(s,1H),10.23(s,1H),11.50(s,1H)。HRMS m/z 530.2410[M+H]+。
1-(4-(6-((4-(6-(1H-吡咯并[2,3-b]吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧 啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮(42)。根据一般合成工序L,通过使42(336mg,501μmol)脱保护制备。黄色固体(186mg,70%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.71(t,2H,J 5.0),2.76(t,2H,J 5.0),3.47(t,2H,J 5.0),3.50(t,2H,J 5.0),6.87(dd,1H,J9.0&3.0),7.03(dd,1H,J 7.5&5.5),7.42(d,1H,J 5.5),7.67(d,1H,J 3.0),7.75(d,1H,J9.0),7.81-7.84(m,2H),7.97(s,1H),8.10(dd,1H,J 7.5&1.5),8.26(dd,1H,J 5.5&1.5),8.47(d,1H,J 5.0),8.55(s,1H),9.70(s,1H),10.27(s,1H),12.01(br s,1H)。HRMS m/z531.2367[M+H]+。
1-(4-(6-((4-(6-碘咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌 嗪-1-基)乙-1-酮(43)。使用一般合成工序I,通过(E)-3-(二甲基氨基)-1-(6-碘咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(342mg,1.00mmol)与2,2,2-三氟乙酸1-(5-(4-乙酰基哌嗪-1-基)吡啶-2-基)胍(452mg,1.20mmol)的反应制备。黄色固体(305mg,56%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.10(t,2H,J 5.0),3.16(t,2H,J 5.0),3.59(t,2H,J 5.5),3.60(t,2H,J5.5),7.42(d,1H,J 5.0),7.50(dd,1H,J 9.0&3.0),7.59(d,1H,J 9.5),7.69(dd,1H,J9.0&1.5),7.89(d,1H,J 9.0),8.13(d,1H,J3.0),8.45(d,1H,J 5.0),8.55(s,1H),10.05(s,1H),10.24(s,1H)。HRMS m/z 541.0951[M+H]+。
1-(4-(6-((4-(咪唑并[1,2-a]吡啶-3-基)-5-甲基嘧啶-2-基)氨基)吡啶-3-基) 哌嗪-1-基)乙-1-酮(44)。使用一般合成工序K,通过3-(2-氯-5-甲基嘧啶-4-基)咪唑并[1,2-a]吡啶(245mg,1.00mmol)与1-(4-(6-氨基吡啶-3-基)哌嗪-1-基)乙-1-酮(232mg,1.05mmol)的反应制备。淡黄色固体(120mg,28%)。1H NMR(DMSO-d6)δ2.05(s,3H),2.43(s,3H),3.07(t,2H,J 4.5),3.14(t,2H,J 4.5),3.59(t,2H,J 4.5),3.60(t,2H,J4.5),7.09(t,1H,J 7.0),7.45(dd,1H,J 9.0&2.0),7.50(t,1H,J 8.0),7.76(d,1H,J 9.0),7.92(d,1H,J 9.0),8.07(d,1H,J 2.0),8.34(s,1H),8.42(s,1H),9.80(s,1H),10.22(d,1H,J7.0)。HRMS m/z 429.2149[M+H]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)嘧啶- 2-胺(45)。使用一般合成工序I,通过(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(295mg,1.00mmol)与1-(5-(4-甲基哌嗪-1-基)吡啶-2-基)胍(555mg,1.20mmol)的反应制备。黄色固体(294mg,63%)。1H NMR(DMSO-d6)δ2.22(s,3H),2.48(t,4H,J 4.0),3.14(t,4H,J 4.0),7.42(d,1H,J 5.5),7.44(dd,1H,J 9.0&2.5),7.60(d,1H,J9.5),7.73(d,1H,J 9.5),7.84(d,1H,J 8.5),8.10(app s,1H),8.45(d,1H,J 5.0),8.63(s,1H),10.10(s,1H),10.29(s,1H)。HRMS m/z465.1145[M(79Br)+H]+,467.1125[M(81Br)+H]+。
N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧 啶-2-胺(46)。使用一般合成工序J,通过45(186mg,400μmol)与苯基硼酸(58.5mg,480μmol)的反应制备。黄色固体(126mg,68%)。1H NMR(DMSO-d6)δ2.22(s,3H),2.43(t,4H,J 4.5),2.96(t,4H,J 5.0),7.11(d,1H,J 8.0),7.41(d,1H,J 5.5),7.44(d,1H,J 7.0),7.48(t,2H,J7.5),7.68(d,2H,J 7.5),7.76(d,1H,J 9.0),7.78-7.84(m,2H),7.84(d,1H,J 9.5),8.46(d,1H,J 5.5),8.58(s,1H),9.88(s,1H),10.18(s,1H)。HRMS m/z 463.2354[M+H]+。
N-(5-溴吡啶-2-基)-4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺(47)。使用一般合成工序I,通过(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(216mg,1.00mmol)与2,2,2-三氟乙酸1-(5-溴吡啶-2-基)胍(395mg,1.20mmol)的反应制备。白色固体(225mg,61%)。1HNMR(DMSO-d6)δ7.15(t,1H,J 7.0),7.51(t,1H,J 8.5),7.53(d,1H,J5.5),7.76(d,1H,J 9.0),7.98(d,1H,J 9.0),8.24(d,1H,J 9.0),8.44(s,1H),8.50(d,1H,J 5.5),8.65(s,1H),10.40(d,1H,J 7.0),10.51(s,1H)。HRMS m/z 367.0308[M(79Br)+H]+,369.0288[M(81Br)+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-基)嘧 啶-2-胺(48)。使用一般合成工序I,通过(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(173mg,804μmol)与2,2,2-三氟乙酸1-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-基)胍(398mg,965μmol)的反应制备。黄色固体(246mg,68%)。1H NMR(DMSO-d6)δ2.94(s,3H),3.26(t,4H,J 5.0),3.27(t,4H,J 5.0),7.12(t,2H,J 7.0),7.43(d,1H,J5.5),7.47-7.53(m,1H),7.76(d,1H,J 9.0),8.05(d,1H,J9.0),8.10(s,1H),8.44(d,1H,J5.5),8.63(s,1H),10.06(s,1H),10.40(d,1H,J 7.0)。HRMS m/z 451.1660[M+H]+。
甲酸1-乙基-4-(6-((4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)铵基)吡啶-3-基) 哌嗪-1-鎓(49)。使用一般合成工序I,通过(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(173mg,804μmol)与2,2,2-三氟乙酸1-(5-(4-乙基哌嗪-1-基)吡啶-2-基)胍(459mg,964μmol)的反应制备,并且通过快速柱色谱法(硅胶,DCM渐变至含DCM:CH3OH:32%NH3的H2O=455:45:1)纯化,然后通过制备型RP-HPLC(梯度0%至25%CH3OH于含0.1%甲酸的H2O溶液中,经20分钟)纯化。黄色固体(60mg,17%)。1H NMR(CD3OD)δ1.32(t,3H,J 7.5),3.01(q,2H,J 7.5),3.18(t,4H,J 5.0),3.39(t,4H,J 5.0),7.11(t,1H,J7.0),7.35(d,1H,J 5.5),7.52(ddd,1H,J 8.5&7.0&1.0),7.54(dd,1H,J 9.0&3.0),7.70(d,1H,J 9.0),7.97(d,1H,J 9.0),8.06(d,1H,J3.0),8.41(d,1H,J 5.5),8.42(s,1H),8.44(s,1H),10.12(d,1H,J 7.0)。HRMS m/z 401.2198[M-HCOO-]+。
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2- 基)嘧啶-2-胺(50)。使用一般合成工序I,通过(E)-1-(6-溴咪唑并[1,2-a]吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(177mg,602μmol)与2,2,2-三氟乙酸1-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-基)胍(298mg,723μmol)的反应制备。黄色固体(225mg,71%)。1H NMR(DMSO-d6)δ2.93(s,3H),3.25(t,4H,J 5.0),3.27(t,4H,J 5.0),7.43(d,1H,J 5.5),7.50(dd,1H,J 9.0&2.5),7.61(d,1H,J 9.5),7.73(d,1H,J9.5),7.89(br d,1H,J 9.0),8.14(d,1H,J 2.5),8.46(d,1H,J 5.0),8.63(s,1H),10.17(s,1H),10.30(s,1H)。HRMS m/z529.0764[M(79Br)+H]+,531.0743[M(81Br)+H]+。
N-(5-氟吡啶-2-基)-4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺(51)。使用一般合成工序I,通过(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(129mg,599μmol)与2,2,2-三氟乙酸1-(5-氟吡啶-2-基)胍(193mg,720μmol)的反应制备。米黄色固体(82mg,44%)。1HNMR(DMSO-d6)δ7.15(t,1H,J 7.0),7.50(d,1H,J 5.5),7.52(t,1H,J7.5),7.73(dd,1H,J 9.0&3.0),7.76(d,1H,J 9.0),8.24(dd,1H,J 9.0&4.0),8.34(d,1H,J 3.0),8.48(d,1H,J 5.5),8.64(s,1H),10.38(s,1H),10.39(d,1H,J 7.5)。HRMS m/z307.1104[M+H]+。
N-(5-氯吡啶-2-基)-4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺(52)。使用一般合成工序I,通过(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(130mg,604μmol)与2,2,2-三氟乙酸1-(5-氯吡啶-2-基)胍(205mg,720μmol)的反应制备。白色固体(68mg,35%)。1H NMR(DMSO-d6)δ7.15(t,1H,J 7.0),7.52(t,1H,J 9.0),7.53(d,1H,J5.5),7.76(d,1H,J 9.0),7.88(d,1H,J 9.0),8.28(d,1H,J 9.0),8.37(s,1H),8.50(d,1H,J 5.5),8.65(s,1H),10.41(d,1H,J 7.0),10.52(s,1H)。HRMS m/z 323.0806[M(35Cl)+H]+,325.0778[M(37Cl)+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-N-(5-碘吡啶-2-基)嘧啶-2-胺(53)。使用一般合成工序I,通过(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(130mg,604μmol)与2,2,2-三氟乙酸1-(5-碘吡啶-2-基)胍(271mg,721μmol)的反应制备。白色固体(41mg,16%)。1H NMR(DMSO-d6)δ7.14(t,1H,J 7.0),7.52(t,1H,J 9.5),7.53(d,1H,J6.0),7.76(d,1H,J 9.0),8.08(d,1H,J 8.5),8.16(d,1H,J 9.0),8.50(d,1H,J5.0),8.54(s,1H),8.66(s,1H),10.42(d,1H,J 7.0),10.49(s,1H)。HRMS m/z 415.0165[M+H]+。
N-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-基)-4-(6-苯基咪唑并[1,2-a]吡啶- 3-基)嘧啶-2-胺(54)。使用一般合成工序J,通过54(159mg,300μmol)与苯基硼酸(43.9mg,360μmol)的反应制备。黄色固体(140mg,89%)。1H NMR(DMSO-d6)δ2.94(s,3H),3.07(t,4H,J4.5),3.22(t,4H,J 4.5),7.16(d,1H,J 8.0),7.42(d,1H,J 5.5),7.46(t,1H,J7.0),7.49(t,2H,J 7.0),7.68(d,2H,J 7.0),7.77(d,1H,J 9.5),7.82-7.88(m,3H),8.47(d,1H,J5.0),8.59(s,1H),9.96(s,1H),10.19(s,1H)。HRMS m/z 527.1970[M+H]+。
4-(咪唑并[1,2-a]吡啶-3-基)-N-(5-甲基吡啶-2-基)嘧啶-2-胺(55)。使用一般合成工序I,通过(E)-3-(二甲基氨基)-1-(咪唑并[1,2-a]吡啶-3-基)丙-2-烯-1-酮(130mg,604μmol)与2,2,2-三氟乙酸1-(5-甲基吡啶-2-基)胍(191mg,723μmol)的反应制备。米黄色固体(70mg,38%)。1HNMR(DMSO-d6)δ2.26(s,3H),7.13(t,1H,J 7.0),7.46(d,1H,J 5.0),7.51(t,1H,J8.5),7.60(d,1H,J 8.5),7.75(d,1H,J 9.0),8.08(d,1H,J8.5),8.18(s,1H),8.46(d,1H,J 5.0),8.62(s,1H),10.14(s,1H),10.42(d,1H,J 6.5)。HRMS m/z303.1361[M+H]+。
1-(4-(6-((4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1- 基)丙-1-酮(56)。向1(92mg,0.25mmol)在CHCl3(10mL)中的悬浮液中添加TEA(36μL,0.26mmol)。将反应混合物在冰浴上冷却,并且滴加丙酰氯(0.22mL,2.5mmol)。将反应混合物升温且在50℃下加热过夜,冷却至室温并且在减压下浓缩。将残余物与含32%NH3的H2O(5mL)混合,在减压下浓缩,并且通过快速柱色谱法(硅胶,DCM渐变至DCM:CH3OH=94:6)纯化,得到为淡黄色固体的61(60mg,57%)。1H NMR(DMSO-d6)δ1.01(t,3H,J 7.5),2.37(q,2H,J 7.5),3.09(t,2H,J 5.0),3.14(t,2H,J 5.0),3.58-3.66(m,4H),7.12(t,1H,J7.0),7.42(d,1H,J 5.5),7.48(dd,1H,J 8.5&2.0),7.51(t,1H,J 8.0),7.75(d,1H,J 9.0),8.03(d,1H,J 9.0),8.08(s,1H),8.44(d,1H,J 5.5),8.62(s,1H),10.02(s,1H),10.39(d,1H,J7.0)。HRMS m/z 429.2145[M+H]+。
1-(4-(6-((4-(6-(1H-吡唑-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡 啶-3-基)哌嗪-1-基)乙-1-酮(57)。使用一般合成工序J,通过10(198mg,401μmol)与3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(93.1mg,480μmol)的反应制备。淡棕色固体(60mg,31%)。1H NMR(DMSO-d6)δ2.05(s,3H),3.02(t,2H,J 5.0),3.08(t,2H,J5.0),3.58(t,2H,J 5.0),3.59(t,2H,J 5.0),6.77(s,1H),7.33(br s,1H),7.43(d,1H,J5.0),7.81(app d,2H,J 9.0),7.96(br s,1H),8.02(app s,2H),8.47(d,1H,J 5.0),8.58(s,1H),9.88(br s,1H),10.23(br s,1H),13.06(br s,1H)。HRMS m/z 481.2199[M+H]+。
1-(4-(6-((4-(6-(1-甲基-1H-吡唑-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基) 氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮(58)。使用一般合成工序J,通过10(198mg,401μmol)与1-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(100mg,481μmol)的反应制备。黄色固体(44mg,22%)。1H NMR(DMSO-d6)δ2.06(s,3H),2.99(t,2H,J 5.0),3.06(t,2H,J 5.0),3.59(app s,4H),3.86(s,3H),6.57(s,1H),7.26(dd,1H,J 8.0&1.0),7.45(d,1H,J 5.5),7.56(s,1H),7.58(d,1H,J 9.5),7.78(s,1H),7.84(d,1H,J 9.0),7.85(d,1H,J 9.0),8.47(d,1H,J 5.5),8.67(s,1H),10.10(s,1H),10.37(s,1H)。HRMS m/z495.2368[M+H]+。
1-(4-(6-((4-(6-(1-(二氟甲基)-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧 啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮(59)。使用一般合成工序J,通过10(198mg,401μmol)与1-(二氟甲基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(117mg,479μmol)的反应制备。黄色固体(156mg,73%)。1H NMR(DMSO-d6)δ2.04(s,3H),3.01(t,2H,J 5.0),3.08(t,2H,J 5.0),3.57(t,2H,J 5.0),3.58(t,2H,J 5.0),7.34(d,1H,J9.0),7.42(d,1H,J 5.5),7.85(app s,2H),7.87(t,1H,J 59.0),7.88-8.02(m,2H),8.32(s,1H),8.45(d,1H,J 5.5),8.58(s,1H),8.85(s,1H),10.08(s,1H),10.19(s,1H)。HRMS m/z 531.2175[M+H]+。
4-(4-(3-(2-((5-(4-乙酰基哌嗪-1-基)吡啶-2-基)氨基)嘧啶-4-基)咪唑并[1, 2-a]吡啶-6-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(60)。使用一般合成工序J,通过10(198mg,401μmol)与4-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯(181mg,480μmol)的反应制备。黄色固体(116mg,44%)。1H NMR(DMSO-d6)δ1.42(s,9H),1.74-1.86(m,2H),2.01-2.06(m,2H),2.05(s,3H),2.94(app brs,2H),3.01(t,2H,J 5.0),3.09(t,2H,J 5.0),3.55-3.60(m,4H),4.06(d,2H,J 11.0),4.32-4.42(m,1H),7.32(dd,1H,J 8.5&2.0),7.40(d,1H,J 5.5),7.73(d,1H,J 9.5),7.77(d,1H,J 9.5),7.88(br s,1H),7.96(d,1H,J 9.0),8.01(d,1H,J 2.0),8.34(s,1H),8.44(d,1H,J 5.5),8.54(s,1H),9.98(s,1H),10.06(s,1H)。HRMS m/z 664.3456[M+H]+。
1-(4-(6-((4-(6-(5-甲基呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨 基)吡啶-3-基)哌嗪-1-基)乙-1-酮(61)。使用一般合成工序J,通过10(198mg,401μmol)与4,4,5,5-四甲基-2-(5-甲基呋喃-2-基)-1,3,2-二氧杂环戊硼烷(100mg,481μmol)的反应制备。黄色固体(140mg,71%)。1H NMR(DMSO-d6)δ2.04(s,3H),2.24(s,3H),3.00(t,2H,J5.0),3.06(t,2H,J 4.0),3.57(t,2H,J 5.0),3.58(t,2H,J 5.0),6.24(d,1H,J 2.5),6.90(d,1H,J 2.5),7.26(dd,1H,J 9.0&2.5),7.41(d,1H,J 5.0),7.75(d,1H,J 9.5),7.80(d,1H,J 9.5),7.94(d,1H,J 9.0),8.01(d,1H,J2.5),8.48(d,1H,J 5.0),8.55(s,1H),9.86(s,1H),10.10(s,1H)。HRMS m/z 495.2244[M+H]+。
4-(6-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-甲基哌嗪-1- 基)吡啶-2-基)嘧啶-2-胺(62)。使用一般合成工序J,通过49(233mg,501μmol)与1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(125mg,601μmol)的反应制备。黄色固体(78mg,33%)。1H NMR(DMSO-d6)δ2.24(s,3H),2.48(t,4H,J 5.0),3.06(t,4H,J5.0),3.89(s,3H),7.29(d,1H,J 9.0),7.40(d,1H,J 5.0),7.70(d,1H,J 9.5),7.77(d,1H,J 9.0),7.94(d,1H,J 9.0),7.96(s,1H),7.98(s,1H),8.15(s,1H),8.43(d,1H,J 5.0),8.55(s,1H),9.96(s,1H),10.06(s,1H)。HRMS m/z 467.2416[M+H]+。
4-(3-(2-((5-(4-乙酰基哌嗪-1-基)吡啶-2-基)氨基)嘧啶-4-基)咪唑并[1,2-a] 吡啶-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(63)。使用一般合成工序J,通过10(198mg,401μmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(149mg,482μmol)的反应制备。米黄色固体(198mg,83%)。1H NMR(DMSO-d6)δ1.42(s,9H),2.04(s,3H),2.45(app s,2H),3.06(t,2H,J 5.0),3.13(t,2H,J5.0),3.52(t,2H,J5.0),3.58(t,2H,J 5.0),3.59(t,2H,J 5.0),3.99(app s,2H),6.19(s,1H),7.39(d,1H,J5.5),7.43(dd,1H,J 9.0&3.0),7.65(d,1H,J 9.5),7.72(d,1H,J 9.5),7.93(d,1H,J9.0),8.04(d,1H,J 2.5),8.45(d,1H,J 5.0),8.54(s,1H),9.83(s,1H),9.86(s,1H)。HRMSm/z596.3094[M+H]+。
6-((4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)-3',6'-二氢-[3,4'-联吡 啶]-1'(2'H)-羧酸叔丁酯(64)。使用一般合成工序J,通过51(147mg,400μmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(149mg,482μmol)的反应制备。淡橙色固体(100mg,53%)。1H NMR(DMSO-d6)δ1.43(s,9H),3.56(t,2H,J5.0),4.02(app s,2H),6.20(s,1H),7.14(t,1H,J 7.0),7.51(d,1H,J 5.5),7.52(td,1H,J 7.0&1.0),7.77(d,1H,J 9.0),7.87(dd,1H,J 8.5&2.0),8.20(d,1H,J 9.0),8.43(d,1H,J 2.0),8.50(d,1H,J 5.5),8.66(s,1H),10.38(s,1H),10.45(d,1H,J 7.0)(两个质子信号(CH2)由于与DMSO残余峰重叠而没有观察到)。HRMS m/z 470.2298[M+H]+。
N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-4-(6-(吡啶-3-基)咪唑并[1,2-a]吡啶-3- 基)嘧啶-2-胺(65)。使用一般合成工序J,通过49(233mg,501μmol)与吡啶-3-基硼酸(73.8mg,600μmol)的反应制备。黄色固体(111mg,48%)。1H NMR(DMSO-d6)δ2.23(s,3H),2.45(t,4H,J 5.0),3.00(t,4H,J 4.5),7.20(d,1H,J 7.5),7.42(d,1H,J 5.0),7.52(dd,1H,J 7.5&5.0),7.81(d,1H,J 9.5),7.85(s,1H),7.88(d,1H,J 9.0),7.91(d,1H,J9.0),8.10(d,1H,J 7.5),8.46(d,1H,J 5.5),8.63(s,1H),8.64(d,1H,J7.0),8.98(s,1H),10.08(s,1H),10.30(s,1H)。HRMS m/z 464.2306[M+H]+。
N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-4-(6-(嘧啶-5-基)咪唑并[1,2-a]吡啶-3- 基)嘧啶-2-胺(66)。使用一般合成工序J,通过49(233mg,501μmol)与5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)嘧啶(124mg,602μmol)的反应制备。黄色固体(175mg,75%)。1HNMR(DMSO-d6)δ2.23(s,3H),2.46(app s,4H),3.05(app s,4H),7.29(d,1H,J 6.5),7.45(d,1H,J 4.0),7.88(d,1H,J 9.5),7.90(s,1H),7.93(d,1H,J 9.0),8.01(d,1H,J 6.0),8.48(d,1H,J 3.5),8.68(s,1H),9.21(s,2H),9.27(s,1H),10.18(br s,1H),10.42(s,1H)。HRMS m/z 465.2263[M+H]+。
4-(6-(1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-甲基哌嗪-1-基)吡 啶-2-基)嘧啶-2-胺(67)。使用一般合成工序J,通过49(233mg,501μmol)与4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑-1-羧酸叔丁酯(177mg,601μmol)的反应制备。黄色固体(80mg,35%)。1H NMR(DMSO-d6)δ2.23(s,3H),2.46(t,4H,J 5.0),3.08(t,4H,J5.0),7.31(dd,1H,J 9.0&1.5),7.40(d,1H,J 5.5),7.77(s,2H),7.99(s,1H),8.00(d,1H,J9.0),8.06(br s,1H),8.37(br s,1H),8.44(d,1H,J5.5),8.56(s,1H),10.04(s,1H),10.11(s,1H),13.07(br s,1H)。HRMS m/z 453.2259[M+H]+。
N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-苯基咪唑并[1,2-a]吡 啶-3-基)嘧啶-2-胺(68)。使用一般合成工序K,通过3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶(250mg,770μmol)与5-((4-乙基哌嗪-1-基)甲基)吡啶-2-胺(181mg,821μmol)的反应制备。米黄色固体(163mg,42%)。1H NMR(DMSO-d6)δ0.98(app s,3H),2.00-2.50(m,10H),3.27(s,2H),7.39(d,1H,J 8.5),7.42-7.51(m,1H),7.47(d,2H,J 7.0),7.68(d,2H,J 6.5),7.85(d,1H,J 8.5),7.86(s,2H),7.20(d,1H,J9.5),8.45(d,1H,J 3.0),8.67(s,1H),10.27(s,1H),10.36(s,1H)。HRMS m/z 509.2572[M+H]+。
N-(5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-基)-5-氟-4-(6-苯基咪唑并[1,2-a] 吡啶-3-基)嘧啶-2-胺(69)。使用一般合成工序K,通过3-(2-氯-5-氟嘧啶-4-基)-6-苯基咪唑并[1,2-a]吡啶(380mg,1.17mmol)与5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-胺(381mg,1.73mol)的反应制备。黄色固体(17mg,3%)。1H NMR(DMSO-d6)δ1.44(app q,2H,J 12.0),1.80(d,2H,J 11.5),2.10-2.20(m,1H),2.20(s,6H),3.43(d,2H,J 11.0),7.09(d,1H,J9.0),7.41-7.51(m,1H),7.47(d,2H,J 7.5),7.66(d,1H,J 8.5),7.68(d,2H,J 7.0),7.73(s,1H),7.84(d,1H,J 9.0),7.90(d,1H,J 9.5),8.41(d,1H,J 3.5),8.61(d,1H,J 2.0),9.99(s,1H),10.20(s,1H)(两种质子信号(CH2)由于与H2O或DMSO残余峰重叠而没有观察到)。HRMS m/z 509.2572[M+H]+。
实施例2生物活性
激酶测定
FLT3(WT)、FLT3(ITD)和FLT3(D835Y)以及CDK的抑制使用ADPGlo激酶测定(Promega Corporation,Madison,WI,USA)确定。例如,FLT3激酶反应分别地用缓冲液(40nMTris碱pH 7.5、20mM MgCl2、0.4mM DTT、0.1mg/mL BSA)、Poly(4:1)Glu,Tyr肽底物、每一种激酶的Km ATP(FLT3-WT:200μM,FLT3-ITD:100μM且FLT3-D835Y:35μM)和每一种FLT3激酶(FLT3-WT:20nM,FLT3-ITD:20nM且FLT3-D835Y:5nM)以5μL的总测定体积进行。制备测试化合物的10种浓度(10μM至0.5nM)1:3的系列稀释液。使激酶反应在室温下进行优化的时间段(FLT3-WT:120分钟,FLT3-ITD:80分钟,FLT3-D835Y:100分钟),然后通过添加5μL ADPGlo试剂终止反应。在室温下黑暗中孵育40分钟后,向每个孔中添加8μL激酶检测试剂并孵育30-40分钟。使用EnVision Multilabel读板仪(PerkinElmer,Buckinghamshire,UK)以1秒/孔的积分时间测量发光。在存在和不存在每一种FLT3激酶的情况下在0.5%DMSO中分别进行阳性对照和阴性对照。类似地,用反应缓冲液(40nMTris碱pH7.5、20mM MgCl2、0.4mMDTT)、0.1mg/ml BSA和RB-CTF底物(视网膜母细胞瘤蛋白1C-末端级分)进行CDK4/D1和CDK6/D3的激酶反应。对于CDK9/细胞周期蛋白T1,用标准测定缓冲液和激酶稀释缓冲液以及RBER-IRStide底物进行激酶反应。半最大抑制(IC50)值使用Graphpad prism(6.0版)的4参数逻辑非线性回归模型计算。表观抑制常数(Ki)值由相应激酶的Km(ATP)和IC50值计算。结果示于表2中。
增殖测定
使来自实施例1的化合物经历对实体肿瘤细胞系和白血病细胞系的标准MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑鎓)和刃天青测定,如先前所报道(Wang S等人,J Med Chem 47:1662-1675,2004以及Diab S.等人,CheMedChem9:962-972,2014)。抑制50%细胞生长所需的化合物浓度(GI50)使用非线性回归分析来计算。结果示于表2中。
表2实施例化合物的酶促活性和细胞活性
(-)未测试
在整个说明书和随附的权利要求书中,除非上下文另有要求,否则词语“包含(comprise)”和“包括(include)”及变型如“包含(comprising)”和“包括(including)”将被理解为暗示包括所陈述的整体或整体的组在内,但不排除任何其他整体或整体的组。
本说明书中对任何现有技术的引用不被认为也不应被认为是承认对此类现有技术形成公知常识的一部分的任何形式的意见。
本领域技术人员将了解的是,本公开的用途不限于所描述的特定应用。本发明也不限于其关于本文描述或叙述的特定要素和/或特征的优选实施方案。还将了解的是,本公开不限于所公开的一个或多个实施方案,而是能够在不脱离由所附权利要求书阐述和限定的本公开的范围的情况下进行多种重新布置、修改和替换。
Claims (18)
1.一种式I化合物:
其中:
R1、R2、R3、R4、R5和R6各自独立选自由以下组成的组:H、烷基、烷基-R7、芳基、芳基-R7、芳烷基、芳烷基-R7、脂环族基、杂芳基、杂环基、卤素、NO2、CN、CF3、OH、O-烷基、COR7、COOR7、O-芳基、O-R7、NH2、NH-烷基、NH-芳基、N-(烷基)2、N-(芳基)2、N-(烷基)(芳基)、NH-R7、NH-烷基-N(烷基)2、N-(R7)(R8)、N-(烷基)(R7)、N-(芳基)(R7)、COOH、CONH2、CONH-烷基、CONH-芳基、CON-(烷基)(R7)、CON(芳基)(R7)、CONH-R7、CON-(R7)(R8)、SH-烷基、SO3H、SO2-烷基、SO2-烷基-R7、SO2-芳基、SO2-芳基-R7、SO2NH2、SO2NH-R7、SO2N-(R7)(R8)、CO-烷基、CO-烷基-R7、CO-芳基、CO-芳基-R7和R9,其中所述烷基、芳基、芳烷基、脂环族基和杂环基基团任选地可以被一个或多个选自以下的基团取代:卤素、CN、OH、烷基(例如C1-6烷基)、O-C1-6烷基(例如O-甲基)、氨基(例如NH2)、COOH、CONH2、CF3CH(F)2或任选地被C1-6烷基、CH(F)2、COO-C1-6烷基(例如COO-C(CH3)3)或苯基磺酰基取代的杂环基基团;并且
R7、R8和R9独立地选自水增溶基团;
或其药学上可接受的盐、溶剂化物或前药。
2.根据权利要求1所述的化合物,其中R1为H、烷基、芳基、CN、CF3、NH2、杂环基、O-烷基、NH-烷基、NH-烷基-N(烷基)2、NH-芳基、N-(烷基)2、N-(烷基)(芳基)、SH-烷基、卤素或R9。
3.根据权利要求2所述的化合物,其中R1为H、C1-3烷基、芳基、CF3或卤素。
4.根据权利要求2所述的化合物,其中R1为任选地被以下基团取代的杂芳基或杂环基基团:C1-6烷基、O-C1-6烷基、氨基、CH(F)2、苯基磺酰基或任选地被C1-6烷基取代的哌嗪。
5.根据权利要求4所述的化合物,其中R1选自任选地被C1-6烷基取代的哌嗪,任选地被C1-6烷基取代的吡啶,任选地被C1-6烷基、O-甲基、NH2或任选地被C1-6烷基或CH(F)2取代的哌嗪、吡咯或吡唑取代的嘧啶,任选地被COO-C1-6烷基取代的哌嗪,任选地被C1-6烷基取代的噻吩基、呋喃,苯并呋喃,苯并噻吩基,任选地被C1-6烷基或苯基磺酰基取代的吲哚以及任选地被苯基磺酰基取代的吡咯并吡啶。
6.根据前述权利要求中任一项所述的化合物,其中R2为H、烷基、CN或卤素。
7.根据前述权利要求中任一项所述的化合物,其中R3、R4、R5和R6中的至少一者为C1-6烷基、卤素、烷基-R7其中R7为SONHCH3或SONHCH2CH3,或NH-R7其中R7为SO2CH3或SO2CH2CH3。
8.根据权利要求1至7中任一项所述的化合物,其中R4或R5为R9。
9.根据权利要求8所述的化合物,其中R9为任选地被一个或多个以下基团取代的含N、O和/或S的杂环基基团:羟基、氨基或烷氧基基团,N(烷基)2,任选地被一个或多个羟基或烷氧基基团取代的NH-烷基,烷基-N(烷基)2,羰基,烷氧基,SO2-烷基,脂肪族,任选地被一个或多个以下基团取代的芳基:氨基、NH-烷基(任选地被一个或多个羟基或烷氧基基团取代)、羧酰胺、亚砜、砜或磺酰胺基团,任选地被一个或多个烷基取代的杂环基,或任选地被一个或多个烷基或羰基取代的NH-杂环基基团,并且其中所述含N、O和/或S的杂环基基团可以任选地包含连接到吡啶基团的烷基桥、氨桥、烷氧基桥或酮桥。
12.一种化合物,其选自由以下组成的组:
1-(4-(6-((4-(咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((5-氟-4-(6-甲基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
N-(5-((4-乙基哌嗪-1-基)甲基)吡啶-2-基)-5-氟-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺;
N-(5-(4-(二甲基氨基)哌啶-1-基)吡啶-2-基)-5-氟-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺;
1-(4-(6-((4-(6-氯咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(三氟甲基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-甲基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯并[b]噻吩-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1H-吡咯-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(呋喃-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(噻吩-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯基氨基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯并呋喃-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(苯并[b]噻吩-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1-甲基-1H-吲哚-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1H-吲哚-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1H-吡咯并[2,3-b]吡啶-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-碘咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺;
4-(6-溴咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-基)嘧啶-2-胺;
N-(5-(4-(甲基磺酰基)哌嗪-1-基)吡啶-2-基)-4-(6-苯基咪唑并[1,2-a]吡啶-3-基)嘧啶-2-胺;
1-(4-(6-((4-(6-(1H-吡唑-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1-甲基-1H-吡唑-3-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
1-(4-(6-((4-(6-(1-(二氟甲基)-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;
4-(4-(3-(2-((5-(4-乙酰基哌嗪-1-基)吡啶-2-基)氨基)嘧啶-4-基)咪唑并[1,2-a]吡啶-6-基)-1H-吡唑-1-基)哌啶-1-羧酸叔丁酯;
1-(4-(6-((4-(6-(5-甲基呋喃-2-基)咪唑并[1,2-a]吡啶-3-基)嘧啶-2-基)氨基)吡啶-3-基)哌嗪-1-基)乙-1-酮;和
4-(6-(1-甲基-1H-吡唑-4-基)咪唑并[1,2-a]吡啶-3-基)-N-(5-(4-甲基哌嗪-1-基)吡啶-2-基)嘧啶-2-胺。
13.如前述权利要求中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药用于治疗癌症或另一种增殖性细胞疾病或病状的用途。
14.一种治疗受试者的癌症或另一种的增殖性细胞疾病或病状的方法,所述方法包括向所述受试者施用治疗有效量的如权利要求1至12中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药,任选地组合有药学上可接受的载剂、稀释剂和/或赋形剂。
15.如权利要求14所述的方法,其中所述欲治疗的增殖性细胞疾病或病状选自特征在于FLT3和/或CDK的过表达和突变的那些。
16.如权利要求1至12中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药在制造用于治疗癌症或另一种的增殖性细胞疾病或病状的药剂中的用途。
17.一种药物组合物或药剂,其包含如权利要求1至12中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药和药学上可接受的载剂、稀释剂和/或赋形剂。
18.一种用于调控细胞中蛋白激酶活性的方法,其包括向所述细胞中引入有效量的如权利要求1至12中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药,或者使所述细胞与有效量的如权利要求1至12中任一项所述的化合物或其药学上可接受的盐、溶剂化物或前药接触。
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